Preface

*Neurons, Dendrites and Axons* is an update of the information that exists about how axons develop and which signaling pathways are involved in the process. This book is divided into five chapters. The first chapter is about axon guidance through the action of the interaction between neurons, as well as the interaction with the extracellular matrix, leading to elucidate the complex connection that exists in the brain during its origin and development. The second chapter is about semaphorins and their relationship with neurodegenerative diseases such as Alzheimer's, Parkinson's, and sclerosis. It also describes the molecular mechanisms that could generate protection as a possible therapy for neurodegenerative diseases. Neurodegenerative diseases and their therapeutic approaches are described in third chapter. The fourth chapter focuses on the gap junction of the dorsal root of the ganglion where the morphology of neurons is described, as well as their neurobiology. Last chapter focuses on the development of bioelectrical nerve interfaces that could be implanted to regenerate damaged nerves.

The editors would like to express their deep gratitude to all the authors who contributed their knowledge to the development of this book. We also thank InTech Publishing for spreading the knowledge worldwide.

> **Dr. Gonzalo Emiliano Aranda Abreu Dr. María Elena Hernández Aguilar** Centro de Investigaciones Cerebrales/Universidad Veracruzana, Xalapa, Veracruz, México

Section 1

Axon Guidance

1

Section 1 Axon Guidance

Chapter 1

Abstract

axonal regeneration

1. Introduction

3

Guidance

Cell-Cell and Cell-Matrix

Interactions during Axons

The establishment of neuronal connections during development is a critical process for the correct function of central nervous system and for their regeneration during adult stages. Axon extension and guidance toward their targets are a complex process involving several signals provided by extracellular milieu where secreted factors, other cells, axons, and extracellular matrix proteins are interacting to establish the wiring of the brain. The expression of those signals at specific time and space, and their mechanisms of action during axon projection are the subject of numerous studies. This knowledge had contributed to understand the complex panorama of brain wiring during development and the origin and possible cure of central nervous system diseases. In this chapter, we focus on cell-cell and cellmatrix interactions as two important signals during axon guidance, and how these interactions impact the response to diffusible guidance cues. We emphasize the need and the challenge to understand the complex relations among simultaneous signals to guide axons projections, and how this knowledge could influence

Keywords: growth cone, guidance cues, fasciculation, extracellular matrix,

After neural tube formation, multipotent stem cells migrate and generate precursor cells that will differentiate into neurons and glial cells. Neurons will extend cell projections to become integrated to the brain circuits by a finely regulated process. Through cell extensions, classified as dendrites and axons, neurons are responsible for the perception of the external world, the former are in charge of receiving electric impulses of other cells, and the last transmit the impulses far from the cell body. Axons projections are stereotyped, and the accuracy of reaching their target is fundamental for the correct central nervous system (CNS) functioning. Axons project by specialized and motile structures located at the end of the axons called growth cones. These specialized regions sense the external milieu, detecting signals that originate complex cellular mechanism involved in axon elongation; therefore, neuronal pathfinding is highly regulated by the availability of the external signals, by the expression of cell receptors, and by specific molecular mechanisms that stimulate or inhibit growth cone displacement. Extracellular matrix

Vela-Alcántara Ana and Tamariz Elisa

approaches to deal with neural regeneration issues.

#### Chapter 1

## Cell-Cell and Cell-Matrix Interactions during Axons Guidance

Vela-Alcántara Ana and Tamariz Elisa

#### Abstract

The establishment of neuronal connections during development is a critical process for the correct function of central nervous system and for their regeneration during adult stages. Axon extension and guidance toward their targets are a complex process involving several signals provided by extracellular milieu where secreted factors, other cells, axons, and extracellular matrix proteins are interacting to establish the wiring of the brain. The expression of those signals at specific time and space, and their mechanisms of action during axon projection are the subject of numerous studies. This knowledge had contributed to understand the complex panorama of brain wiring during development and the origin and possible cure of central nervous system diseases. In this chapter, we focus on cell-cell and cellmatrix interactions as two important signals during axon guidance, and how these interactions impact the response to diffusible guidance cues. We emphasize the need and the challenge to understand the complex relations among simultaneous signals to guide axons projections, and how this knowledge could influence approaches to deal with neural regeneration issues.

Keywords: growth cone, guidance cues, fasciculation, extracellular matrix, axonal regeneration

#### 1. Introduction

After neural tube formation, multipotent stem cells migrate and generate precursor cells that will differentiate into neurons and glial cells. Neurons will extend cell projections to become integrated to the brain circuits by a finely regulated process. Through cell extensions, classified as dendrites and axons, neurons are responsible for the perception of the external world, the former are in charge of receiving electric impulses of other cells, and the last transmit the impulses far from the cell body. Axons projections are stereotyped, and the accuracy of reaching their target is fundamental for the correct central nervous system (CNS) functioning. Axons project by specialized and motile structures located at the end of the axons called growth cones. These specialized regions sense the external milieu, detecting signals that originate complex cellular mechanism involved in axon elongation; therefore, neuronal pathfinding is highly regulated by the availability of the external signals, by the expression of cell receptors, and by specific molecular mechanisms that stimulate or inhibit growth cone displacement. Extracellular matrix

components present in axons pathway can be signaling by forming soluble chemotropic protein gradients and/or by direct interaction with membrane receptors at the growth cones. Besides, other axons present in the pathway could be promoting axons-axons interactions or fasciculation, allowing the guidance of projections toward their final targets. In this chapter, we make a rough description of cellular mechanisms of growth cone motility that drives axon elongation, mainly focused in the cell adhesion and cytoskeleton regulation by guidance cues, followed by some of the evidences about cell-extracellular matrix and cell-cell interactions relevance during axons projection; finally, we address the importance of synergic interaction among the signals, and how they can modulate the response of axons during pathfinding toward their targets.

force projection; therefore, MT advances while the C domain transforms in an axon segment, consolidating the axon elongation [9]. Cytoskeleton dynamics and cell adhesion regulation therefore are very important during the response to

Cell-Cell and Cell-Matrix Interactions during Axons Guidance

DOI: http://dx.doi.org/10.5772/intechopen.79681

cues [10–12].

2.1 Cell-extracellular matrix interactions

cell-anchored proteins as axon guidance cues.

5

guidance cues, for example, at the side of the growth cone turning toward an attractant cue, a stabilization and a decrease of F-actin retrograde flow and anchoring through adhesion sites is present, while the inhibition of F-actin and MT polymerization occurs at the growth cone side retracted in response to a repulsive guidance

Adhesion of growth cones to the substrate is finely regulated during axon elongation or retraction. Adhesion sites or "contact points" (CP) are constituted by protein complexes that allow the adhesion and generation of traction force on the substrate [13]; these complexes mediate the anchoring of cells by the transmembrane protein integrins that have a primordial role, coupling the cytoskeleton to the extracellular matrix and by recruiting adaptor and signaling proteins at the cytosolic side [14]. Adhesion complexes include several associated proteins that mediate the interactions with the cytoskeleton, regulate actin polymerization, and participate in the signaling exerted by cell adhesion [2, 14, 15]. During axon projection, assemblydisassembly of CP are involved in response to guidance cues; the inhibition of turnover of CP inhibits axons outgrowth, while localized assembly and turnover of CP promote axon extension in response to guidance cues [13, 16, 17], for example, activation of integrins and subsequent focal adhesion kinase (FAK) phosphorylation are involved in the attraction of dendrites mediated by the chemotrophic protein semaphorin 3A [18], while repellant factors as myelin-associated glycoprotein (MAG) induce growth cone turning by a rapid endocytosis of integrins and loss of cell adhesions [19]. In summary, the projection or retraction of growth cones responds to extracellular signals that guide them to specific targets and trigger a complex network of signal transduction mechanisms that includes the dynamic remodeling of cell adhesion sites and cytoskeleton that together translate into elongation or retraction movements for the redirection of the neuronal projections.

As mentioned earlier, neurons project their neurites to specific targets, guided by extracellular signals integrated by the growth cone. The mechanisms to direct axons projection are triggered by secreted chemotropic proteins, by proteins anchored to the substrate, or by direct interactions between axons mediated by proteins anchored to the cell membrane, as cell adhesion proteins or even chemotropic protein receptors [20, 21]. Growth cones respond to gradients of diffusible molecules, or of proteins associated with the substrate, that guide them to the innervation target; these molecules can be chemoattractive or chemorepellant, and the extracellular matrix can stabilize the gradients from target cells or interme-

diate cells, extending them at a greater distance [21]. Although classical

chemotropic proteins as ephrins, netrins, slits, and semaphorins are some of the more studied guidance cues, in this chapter, we focus our attention to ECM and

The interaction with extracellular matrix (ECM) components was one of the first proposed axon guidance cues that exert a "contact guidance" effect, improving axon projection [22]. ECM components surround cells and are distributed along the pathways of axon projection [23, 24]; therefore, they are not only part of the support in which neurons are divided and maintained but also has a relevant role in the signaling and the determination of the differentiation and migration of neurons, and in the elongation processes of neurites [25–27]. In addition, the physical

#### 2. Cellular mechanisms of axon projection

The growth cone is a specialized structure located at the end of axons or dendrites, capable to detect extracellular guidance cues and to integrate them into a projection or retraction movement that guides the axon toward their innervation target [1]. During axonal elongation, changes in the growth cone morphology and in the direction of its projection depend on the cytoskeleton dynamics and on the regulation of cell adhesion, inducing the formation of filopodia and lamellipodia at the leading edge and exerting tensile and traction forces that will influence neuron elongation [2, 3]. According to the cytoskeleton distribution, the growth cone can be divided into three structural domains: the central domain (C domain), in which there are stable microtubule (MT) bundles entering the growth cone from the axon axis, organelles, vesicles and actin bundles; the peripheral domain (P domain), located in the distal part of the growth cone, containing actin filaments (F-actin bundles) that form the filopodia and lamellipodia, and dynamic MT that extends from the C domain and invades the P domain following the F-actin bundles. Finally, the intermediate zone between the C and P domain called the transition zone (T zone), which contains actomyosin contractile structures located perpendicular to the F-actin bundles [4, 5].

The lamellipodia and filopodia are dynamic structures, from which the elongation process starts. Lamellipodia are broader structures, rich in actin filament networks, while the filopodia are thin extensions, about 100–200 nm diameter and 10 μm in length, constituted by a 10–30 very close actin filaments arranged in parallel [5]. The rate of F-actin and MT polymerization and the retrograde flow of F-actin determine the extension and retraction of the growth cone. In a rough description, actin monomers assemble into F-actin filaments at the cell membrane boundary of the P zone, pushing the membrane during the elongation, thus generating tensile forces. By a retrograde flow driven by actomyosin contractility and by the cell-extracellular matrix interaction, filaments push themselves backward to the T region where filaments are severed and recycled [2, 5, 6]. Assembly and disassembly of the F-actin filaments by controlling the polymerization rate of globular monomeric actin (G-actin) are important for the advance or retraction and is influenced by guidance cues [7, 8]. At the same time, MT plus ends point toward axon tips, and their assembly and disassembly at growth cone are regulated by the F-actin bundles and by the traction force exerted by the actomyosin contractility, allowing the capture and guidance of MT extension through the T and P domain, stabilizing the filopodia [5]. MT polymerization and invasion of P domain, coupled to substrate anchor of growth cone projections by cell adhesion sites linked to the cytoskeleton, promotes growth cone, pulling forward using the actomyosin-mediated

#### Cell-Cell and Cell-Matrix Interactions during Axons Guidance DOI: http://dx.doi.org/10.5772/intechopen.79681

components present in axons pathway can be signaling by forming soluble

during pathfinding toward their targets.

Neurons - Dendrites and Axons

to the F-actin bundles [4, 5].

4

2. Cellular mechanisms of axon projection

chemotropic protein gradients and/or by direct interaction with membrane receptors at the growth cones. Besides, other axons present in the pathway could be promoting axons-axons interactions or fasciculation, allowing the guidance of projections toward their final targets. In this chapter, we make a rough description of cellular mechanisms of growth cone motility that drives axon elongation, mainly focused in the cell adhesion and cytoskeleton regulation by guidance cues, followed by some of the evidences about cell-extracellular matrix and cell-cell interactions relevance during axons projection; finally, we address the importance of synergic interaction among the signals, and how they can modulate the response of axons

The growth cone is a specialized structure located at the end of axons or dendrites, capable to detect extracellular guidance cues and to integrate them into a projection or retraction movement that guides the axon toward their innervation target [1]. During axonal elongation, changes in the growth cone morphology and in the direction of its projection depend on the cytoskeleton dynamics and on the regulation of cell adhesion, inducing the formation of filopodia and lamellipodia at the leading edge and exerting tensile and traction forces that will influence neuron elongation [2, 3]. According to the cytoskeleton distribution, the growth cone can be divided into three structural domains: the central domain (C domain), in which there are stable microtubule (MT) bundles entering the growth cone from the axon axis, organelles, vesicles and actin bundles; the peripheral domain (P domain), located in the distal part of the growth cone, containing actin filaments (F-actin bundles) that form the filopodia and lamellipodia, and dynamic MT that extends from the C domain and invades the P domain following the F-actin bundles. Finally, the intermediate zone between the C and P domain called the transition zone (T zone), which contains actomyosin contractile structures located perpendicular

The lamellipodia and filopodia are dynamic structures, from which the elongation process starts. Lamellipodia are broader structures, rich in actin filament networks, while the filopodia are thin extensions, about 100–200 nm diameter and 10 μm in length, constituted by a 10–30 very close actin filaments arranged in parallel [5]. The rate of F-actin and MT polymerization and the retrograde flow of F-actin determine the extension and retraction of the growth cone. In a rough description, actin monomers assemble into F-actin filaments at the cell membrane boundary of the P zone, pushing the membrane during the elongation, thus generating tensile forces. By a retrograde flow driven by actomyosin contractility and by the cell-extracellular matrix interaction, filaments push themselves backward to the T region where filaments are severed and recycled [2, 5, 6]. Assembly and disassembly of the F-actin filaments by controlling the polymerization rate of globular monomeric actin (G-actin) are important for the advance or retraction and is influenced by guidance cues [7, 8]. At the same time, MT plus ends point toward axon tips, and their assembly and disassembly at growth cone are regulated by the F-actin bundles and by the traction force exerted by the actomyosin contractility, allowing the capture and guidance of MT extension through the T and P domain, stabilizing the filopodia [5]. MT polymerization and invasion of P domain, coupled to substrate anchor of growth cone projections by cell adhesion sites linked to the cytoskeleton, promotes growth cone, pulling forward using the actomyosin-mediated force projection; therefore, MT advances while the C domain transforms in an axon segment, consolidating the axon elongation [9]. Cytoskeleton dynamics and cell adhesion regulation therefore are very important during the response to guidance cues, for example, at the side of the growth cone turning toward an attractant cue, a stabilization and a decrease of F-actin retrograde flow and anchoring through adhesion sites is present, while the inhibition of F-actin and MT polymerization occurs at the growth cone side retracted in response to a repulsive guidance cues [10–12].

Adhesion of growth cones to the substrate is finely regulated during axon elongation or retraction. Adhesion sites or "contact points" (CP) are constituted by protein complexes that allow the adhesion and generation of traction force on the substrate [13]; these complexes mediate the anchoring of cells by the transmembrane protein integrins that have a primordial role, coupling the cytoskeleton to the extracellular matrix and by recruiting adaptor and signaling proteins at the cytosolic side [14]. Adhesion complexes include several associated proteins that mediate the interactions with the cytoskeleton, regulate actin polymerization, and participate in the signaling exerted by cell adhesion [2, 14, 15]. During axon projection, assemblydisassembly of CP are involved in response to guidance cues; the inhibition of turnover of CP inhibits axons outgrowth, while localized assembly and turnover of CP promote axon extension in response to guidance cues [13, 16, 17], for example, activation of integrins and subsequent focal adhesion kinase (FAK) phosphorylation are involved in the attraction of dendrites mediated by the chemotrophic protein semaphorin 3A [18], while repellant factors as myelin-associated glycoprotein (MAG) induce growth cone turning by a rapid endocytosis of integrins and loss of cell adhesions [19]. In summary, the projection or retraction of growth cones responds to extracellular signals that guide them to specific targets and trigger a complex network of signal transduction mechanisms that includes the dynamic remodeling of cell adhesion sites and cytoskeleton that together translate into elongation or retraction movements for the redirection of the neuronal projections.

#### 2.1 Cell-extracellular matrix interactions

As mentioned earlier, neurons project their neurites to specific targets, guided by extracellular signals integrated by the growth cone. The mechanisms to direct axons projection are triggered by secreted chemotropic proteins, by proteins anchored to the substrate, or by direct interactions between axons mediated by proteins anchored to the cell membrane, as cell adhesion proteins or even chemotropic protein receptors [20, 21]. Growth cones respond to gradients of diffusible molecules, or of proteins associated with the substrate, that guide them to the innervation target; these molecules can be chemoattractive or chemorepellant, and the extracellular matrix can stabilize the gradients from target cells or intermediate cells, extending them at a greater distance [21]. Although classical chemotropic proteins as ephrins, netrins, slits, and semaphorins are some of the more studied guidance cues, in this chapter, we focus our attention to ECM and cell-anchored proteins as axon guidance cues.

The interaction with extracellular matrix (ECM) components was one of the first proposed axon guidance cues that exert a "contact guidance" effect, improving axon projection [22]. ECM components surround cells and are distributed along the pathways of axon projection [23, 24]; therefore, they are not only part of the support in which neurons are divided and maintained but also has a relevant role in the signaling and the determination of the differentiation and migration of neurons, and in the elongation processes of neurites [25–27]. In addition, the physical

properties of ECM as topography and stiffness have now an increasing interest as factors that influence axon projection [28].

collagen IV and laminin, and changes in glial intermediate filaments as vimentin

Besides stiffness, ECM topography is also a factor that determines the orientation and projection of neurites. Since early observation about the alignment and orientation of axons by "contact guidance," and the improving of axon elongation by aligned collagen fibrils [22, 67], advance in micro- and nanofabrication of biocompatible fibrous substrates, with specific topography and orientation, has shown to improve neurite elongation and orientation, promoting nerve regeneration [68]. Fibers alignment and dimensions are important to improve axonal guidance and elongation, for example, the micrometer versus nanometer dimensions of poly(lactic-glycolic acid) PLGA fibers improve the alignment of neurites [69], and aligned versus nonaligned gelatin and chitosan fibers induce a higher formation of filopodia in Schwann cells, improving the orientation of axon projections along

During the first stages of CNS formation, neuron clusters projects pioneering axons to form longitudinal, transversal, and commissural tracts [71], functioning as scaffolds for latter or follower axons. Early axon scaffolds are well conserved in vertebrates, and common tracts had been described in zebrafish, chick, mouse, sea lamprey, and others. Among common tracts, the ventral longitudinal tract (VLT) formed by the medial longitudinal fascicle (MLF) and the tracts of the post-optic commissure (TPOC) are present in all the studied vertebrates. In amniotes, there are five early axon scaffolds: the MLF, the TPOC, the mammillo-tegmental tract (MTG), the tract of the posterior commissure (TPC), and the tract of the mesence-

phalic nucleus of the trigeminal nerve (DTmesV) [72]. Axons scaffolds are established as early as embryonic day (E) 8.5 for the DTmesV or E9.5 for MLF in mouse, soon after neural tube closure [73]. Axon-axon interactions are regulated during axon projection, and fasciculation and de-fasciculation could be present along the neural pathfinding, as reported early in insect embryos as grasshopper [74] or fruit fly Drosophila [75]. Fasciculation is a regulated process since growth cones can distinguish among different fascicles, and this behavior is driven by the recognition of cell adhesion molecules, as will be mentioned ahead, mediating a stereotyped targeting. Axons fasciculation can be a permissive or a repulsive cue, promoting or inhibiting axon projection by guiding axons through previously established "routes" by pioneering axons, or by limiting axon projections away of the previously established fascicles. Pioneering axons therefore become an important guidance cue that can determine the routes and the correct pattern of tracts [76]; moreover, their growth cones exhibit different morphology as compared with growth cones of follower axons, and a different speed while approaching the midline at the post-optic commissure in zebrafish embryos, indicating that the response to guidance cues as extracellular matrix or chemotropic proteins is different in pioneering and follower axons, probably by modifying their accessibility or sensibility to the guidance cues [77]; however, if the pioneering axons are eliminated, follower axons can convert to pioneering to establish normal tracts [77, 78].

Axons fasciculation is mediated by cell adhesion proteins (CAMs). CAMs are proteins linked to cell membrane as transmembrane proteins or as GPI-anchored proteins, with homophilic or heterophilic interactions [79]. Among the most relevant CAMs are the members of the calcium-independent cell adhesion immunoglobulin superfamily, like neural cell adhesion proteins (NCAM), several proteins of L1 family as L1, CHL1, neurofascin and NrCAM, and a member of the classic

and GFAP, soften the tissue at the scar [66].

DOI: http://dx.doi.org/10.5772/intechopen.79681

Cell-Cell and Cell-Matrix Interactions during Axons Guidance

the fibers [70].

7

2.2 Cell-cell interactions

ECM comprises about 40% of extracellular space in developing brains as compared with the 20% in adult brains [29]. Some of the most relevant ECM proteins implicated in axonal projection are laminin, fibronectin, collagen, and tenascin. Laminins are a heterotrimeric glycoproteins family, formed of α, β, and γ subunits. During CNS development, laminins have an important role in promoting cell migration and axonal outgrowth [26], and the absence of laminins results in important axon-targeting alterations [30–32]. Fibronectin is a glycoprotein present in the early development at central and peripheral nervous system in the spinal cord and cortex [33, 34] and is involved in cell migration, cell adhesion, and in stimulation of neurite outgrowth during development and after peripheral nervous system injury [35–37]. Both laminins and fibronectin have an important role in modulating the response to chemotropic proteins [38, 39]. Collagen is a family of fibrillar glycoproteins that gives structure and support to cells as well as anchorage for other proteins [40, 41]. Collagens have an important role in neurite outgrowth, axon guidance, and axon targeting, and their absence impacts central and peripheral axons, targeting as a motor axon guidance and retinal ganglion cell projection [42–44]. Tenascin is another ECM glycoprotein family with several functional domains [45]. In vitro and in vivo experiments have shown an inhibitory effect of tenascin for several kinds of axons as hippocampal and cerebellar neurons [46, 47]; however, specific alternative spliced variants promote neurite outgrowth, as the fibronectin type-III domain of tenascin C that induce cerebellar neurons outgrowth [48]. Chondroitin sulfate proteoglycans (CSPGs) are ECM proteoglycans with both inhibitory and attractant effects on axonal outgrowth. The accumulation of CSPG in scar tissue, after injuries in adult CNS, inhibits axon outgrowth [49]; however, it is also a permissive signal along axonal pathways during the development of retinal projection, or in the cortex [50–53], and their inhibitory effects are attenuated by the presence of laminin-1 [54, 55].

Recent studies have shown that the ECM stiffness determines cellular processes such as differentiation, proliferation, and migration [56–58]. Particularly, the work of Engler et al. demonstrated for the first time that the stiffness of the substrate in which stem cells are grown in vitro can modulate their differentiation into cell types such as bone, muscle, or neurons [59]. Probably, one of the first studied aspects has been the role of stiffness in the elongation of neurites; Flanagan et al. reported that when primary neurons of the mouse spinal cord (E13.5) grew in matrices with less stiffness, close to that found in the brain, the elongation of the neurites was greater [60]. However, there are divergences in the data depending on the model, since it has been reported that on softer substrates, PC12 cells show few neurites, relatively short and unbranched, whereas on stiffer substrates, cortical neurons and astrocytes (E17-E19) turn out to have longer and branched projections [57, 60, 61].

In the case of developing nervous system, variations in stiffness during development stages, and at different regions as cerebral cortex and optic tectum have been reported [62, 63]. Guidance by chemotropic proteins as slits and semaphorins of retinal ganglion cell (RGC) axons projecting from the retina to the optic tectum (OT) has been extensively reported [64, 65]; interestingly, tissue stiffness also determines their projection, since RGC axons project toward softer OT and grow as fascicles while traversing stiffer regions. Once the axons arrive at the OT, the softer tissue slows down the projections and splays apart the fascicles to branch them and to form synapses with their stereotypic targets [63]. On the other hand, the prevention of axon regeneration after injury can be in part due to changes in ECM and tissue stiffness, as shown for glial scar after spinal cord injury, where components as

#### Cell-Cell and Cell-Matrix Interactions during Axons Guidance DOI: http://dx.doi.org/10.5772/intechopen.79681

collagen IV and laminin, and changes in glial intermediate filaments as vimentin and GFAP, soften the tissue at the scar [66].

Besides stiffness, ECM topography is also a factor that determines the orientation and projection of neurites. Since early observation about the alignment and orientation of axons by "contact guidance," and the improving of axon elongation by aligned collagen fibrils [22, 67], advance in micro- and nanofabrication of biocompatible fibrous substrates, with specific topography and orientation, has shown to improve neurite elongation and orientation, promoting nerve regeneration [68]. Fibers alignment and dimensions are important to improve axonal guidance and elongation, for example, the micrometer versus nanometer dimensions of poly(lactic-glycolic acid) PLGA fibers improve the alignment of neurites [69], and aligned versus nonaligned gelatin and chitosan fibers induce a higher formation of filopodia in Schwann cells, improving the orientation of axon projections along the fibers [70].

#### 2.2 Cell-cell interactions

properties of ECM as topography and stiffness have now an increasing interest as

ECM comprises about 40% of extracellular space in developing brains as compared with the 20% in adult brains [29]. Some of the most relevant ECM proteins implicated in axonal projection are laminin, fibronectin, collagen, and tenascin. Laminins are a heterotrimeric glycoproteins family, formed of α, β, and γ subunits. During CNS development, laminins have an important role in promoting cell migration and axonal outgrowth [26], and the absence of laminins results in important axon-targeting alterations [30–32]. Fibronectin is a glycoprotein present in the early development at central and peripheral nervous system in the spinal cord and cortex [33, 34] and is involved in cell migration, cell adhesion, and in stimulation of neurite outgrowth during development and after peripheral nervous system injury [35–37]. Both laminins and fibronectin have an important role in modulating the response to chemotropic proteins [38, 39]. Collagen is a family of fibrillar glycoproteins that gives structure and support to cells as well as anchorage for other proteins [40, 41]. Collagens have an important role in neurite outgrowth, axon guidance, and axon targeting, and their absence impacts central and peripheral axons, targeting as a motor axon guidance and retinal ganglion cell projection [42–44]. Tenascin is another ECM glycoprotein family with several functional domains [45]. In vitro and in vivo experiments have shown an inhibitory effect of tenascin for several kinds of axons as hippocampal and cerebellar neurons [46, 47]; however, specific alternative spliced variants promote neurite outgrowth, as the fibronectin type-III domain of tenascin C that induce cerebellar neurons outgrowth [48]. Chondroitin sulfate proteoglycans (CSPGs) are ECM proteoglycans with both inhibitory and attractant effects on axonal outgrowth. The accumulation of CSPG in scar tissue, after injuries in adult CNS, inhibits axon outgrowth [49]; however, it is also a permissive signal along axonal pathways during the development of retinal projection, or in the cortex [50–53], and their inhibitory effects are attenuated by

Recent studies have shown that the ECM stiffness determines cellular processes such as differentiation, proliferation, and migration [56–58]. Particularly, the work of Engler et al. demonstrated for the first time that the stiffness of the substrate in which stem cells are grown in vitro can modulate their differentiation into cell types such as bone, muscle, or neurons [59]. Probably, one of the first studied aspects has been the role of stiffness in the elongation of neurites; Flanagan et al. reported that when primary neurons of the mouse spinal cord (E13.5) grew in matrices with less stiffness, close to that found in the brain, the elongation of the neurites was greater [60]. However, there are divergences in the data depending on the model, since it has been reported that on softer substrates, PC12 cells show few neurites, relatively short and unbranched, whereas on stiffer substrates, cortical neurons and astrocytes

(E17-E19) turn out to have longer and branched projections [57, 60, 61].

In the case of developing nervous system, variations in stiffness during development stages, and at different regions as cerebral cortex and optic tectum have been reported [62, 63]. Guidance by chemotropic proteins as slits and semaphorins of retinal ganglion cell (RGC) axons projecting from the retina to the optic tectum (OT) has been extensively reported [64, 65]; interestingly, tissue stiffness also determines their projection, since RGC axons project toward softer OT and grow as fascicles while traversing stiffer regions. Once the axons arrive at the OT, the softer tissue slows down the projections and splays apart the fascicles to branch them and to form synapses with their stereotypic targets [63]. On the other hand, the prevention of axon regeneration after injury can be in part due to changes in ECM and tissue stiffness, as shown for glial scar after spinal cord injury, where components as

factors that influence axon projection [28].

Neurons - Dendrites and Axons

the presence of laminin-1 [54, 55].

6

During the first stages of CNS formation, neuron clusters projects pioneering axons to form longitudinal, transversal, and commissural tracts [71], functioning as scaffolds for latter or follower axons. Early axon scaffolds are well conserved in vertebrates, and common tracts had been described in zebrafish, chick, mouse, sea lamprey, and others. Among common tracts, the ventral longitudinal tract (VLT) formed by the medial longitudinal fascicle (MLF) and the tracts of the post-optic commissure (TPOC) are present in all the studied vertebrates. In amniotes, there are five early axon scaffolds: the MLF, the TPOC, the mammillo-tegmental tract (MTG), the tract of the posterior commissure (TPC), and the tract of the mesencephalic nucleus of the trigeminal nerve (DTmesV) [72]. Axons scaffolds are established as early as embryonic day (E) 8.5 for the DTmesV or E9.5 for MLF in mouse, soon after neural tube closure [73]. Axon-axon interactions are regulated during axon projection, and fasciculation and de-fasciculation could be present along the neural pathfinding, as reported early in insect embryos as grasshopper [74] or fruit fly Drosophila [75]. Fasciculation is a regulated process since growth cones can distinguish among different fascicles, and this behavior is driven by the recognition of cell adhesion molecules, as will be mentioned ahead, mediating a stereotyped targeting. Axons fasciculation can be a permissive or a repulsive cue, promoting or inhibiting axon projection by guiding axons through previously established "routes" by pioneering axons, or by limiting axon projections away of the previously established fascicles. Pioneering axons therefore become an important guidance cue that can determine the routes and the correct pattern of tracts [76]; moreover, their growth cones exhibit different morphology as compared with growth cones of follower axons, and a different speed while approaching the midline at the post-optic commissure in zebrafish embryos, indicating that the response to guidance cues as extracellular matrix or chemotropic proteins is different in pioneering and follower axons, probably by modifying their accessibility or sensibility to the guidance cues [77]; however, if the pioneering axons are eliminated, follower axons can convert to pioneering to establish normal tracts [77, 78].

Axons fasciculation is mediated by cell adhesion proteins (CAMs). CAMs are proteins linked to cell membrane as transmembrane proteins or as GPI-anchored proteins, with homophilic or heterophilic interactions [79]. Among the most relevant CAMs are the members of the calcium-independent cell adhesion immunoglobulin superfamily, like neural cell adhesion proteins (NCAM), several proteins of L1 family as L1, CHL1, neurofascin and NrCAM, and a member of the classic

calcium-dependent cadherins family, N-cadherin [20, 79]. The regulation of axons fasciculation could be exerted by modifying CAM expression or by modifying CAM interactions by post-translational modifications, as the addition of polysialic acid to NCAM (PSA-NCAM) [80]. Enhancement of axonal outgrowth has been previously shown by culturing neurons over transfected fibroblast expressing NCAM, Ncadherin, or L1 [81–83], allowing homophilic interactions of CAM expressed in fibroblasts and axon. CAMs also establish heterophilic interactions among proteins as integrin β1 [84], and receptors of chemotropic proteins as the ephrin receptors, EphA3, EphA4 [85], or semaphorins receptor, neuropilin-1 (Npn-1) with L1 [86], or EphA7 receptor with CHL1 [85], modulating the response to chemotropic proteins but also their adhesion. It has been shown that Npn-1, a receptor for class 3 semaphorins, is involved in the fasciculation of motor and sensory axons during limb innervation, and the selective depletion of Npn-1 in dorsal root ganglion neurons leads to defasciculation of motor projections, even when motor neurons still express Npn1, resulting in dorso-ventral incorrect targeting of motor neurons [87]. Npn-1 depletion also affects fasciculation and targeting of cranial nerves and Schwann cells migration [87]. Interestingly, altered projections of descending GAD65-positive fascicles from the MTG tract, present in double knockout mice for Slit chemotropic protein receptors Robo1/2, modify the nigrostriatal projection (NP) of dopaminergic neurons, impairing both tracts interactions, probably by the absence of homophilic Robo-Robo interactions and heterophilic interaction with NCAM proteins [88], explaining some of the Slit1/2 independent role of Robo-expressing axons during NP projection [89]. These results show that besides their role of mediating attraction or repulsive responses, some receptors for chemotropic proteins also mediate axons fasciculation by homo- and heterophilic interactions, and this role could be concealed or dismissed by the more characterized chemotropic response. Moreover, the absence of the expression of receptors Npn-1 and 2 in some of the DA axons projecting to the striatum and driven by semaphorins during NP formation suggests that fasciculation could be a relevant mechanism of guidance for these axons, and a complementary strategy for the projection of DA axons in addition to the chemotropic response [90]. dependent on the integrin expression, since a differential expression of α7 integrin

The generated knowledge about guidance cues as chemotropic proteins and ECM in axon guidance has led to multiple approaches to use them into the regeneration of CNS [95–97]. When the axonal continuity is interrupted by an injury or a disease, a correct axonal regeneration is required to effectively restore the nerve; in this process, cells and ECM interactions, chemotropic proteins, and factors as substrate stiffness are important. In vitro use of ECM as fibronectin has shown to support mouse cortical and hippocampal neurons axonal outgrowth mediated by α5β1 integrin [98]; in vivo application of fibrin/fibronectin gel at the rat spinal cord injury site is permissive to axonal outgrowth [99], and when fibrin glue is applied as a microsurgery suture at a sciatic nerve transplantation model in mouse, axons were more branched and travel longer distances reducing the regeneration time [100]. In the area of biomaterials engineering for axonal regeneration, several approaches promote neural outgrowth, combining ECM components and neurotrophic factors as laminin plus microspheres with neural growth factor and neurotrophin-3 for the repair of sciatic nerve in rats [101], or carbon-coated microfibers plus basic fibroblast growth factor and fibronectin for spinal cord injury [102]; moreover, the integration of stiffness, porosity, and adhesion promotion shows that an approach considering multiple factors can help to promote and orient axon outgrowth [103], and a soft and aligned fibrillary fibrin hydrogel promotes and directs axonal projection in a spinal cord injury in mouse [104]. The big challenge therefore is to integrate several cues to obtain a better and controlled growth cone response; the desired response could be obtained by developing biocompatible materials that allow an adequate scaffold containing both the

in the subpopulations of DRG determines their response to NGF and NT-3 neurotrophin [93]. Semaphorin 3D, a repulsive chemotropic protein, can regulate MLF axons fasciculation by regulating the expression of L1 CAM in zebrafish, suggesting that besides the reported repulsive effects of semaphorins, their action could be exerted by the regulating expression of cell adhesion molecules [32]. Moreover, a complex interrelation among ECM, response to neurotropic factors, and cell-cell interactions has been reported for chick embryo DRG axons from in vitro explants cultured over a bioactive substrate; the NGF-induced outgrowth of DRG axons and Schwann cells from tissue explants was dependent on the density of the Arg-Gly-Asp (RGD) integrin-binding domain of fibronectin, and this effect was mediated by the upregulation of L1 and NCAM proteins by NGF that allowed the

interactions among DRG neurons and Schwann cells [94].

Cell-Cell and Cell-Matrix Interactions during Axons Guidance

DOI: http://dx.doi.org/10.5772/intechopen.79681

chemical and physical cues, to allow an effective neural regeneration.

Educational Council Program PRODEP for their financial support.

The authors declare no conflict of interest.

V-A. A. is a student of the Health Science Ph. D. program of the Universidad Veracruzana and receive the CONACYT scholarship number 297485. The authors acknowledge the Universidad Veracruzana Health Science Ph. D. program and the

Acknowledgements

Conflict of interest

9

4. Guidance cues during regeneration

#### 3. Synergic effects of guidance cues

As mentioned before, chemotropic proteins, extracellular matrices, and axon fasciculation are the main guidance cues during axon projection, their effects and mechanisms of action had been mainly studied as a separated stimulus by in vitro assays in explants or cell cultures, or in knockout animals; however, the panorama of axon projection during CNS formation implies simultaneous guidance cues, and projecting neurons should be responding and adapting according to all of them. Interactions among ECM with secreted chemotropic factors can modify their effects on axon projection, for example, it has been shown that the attraction response of RGC to chemotropic protein netrin-1 can be modified to repulsion after neurons interact with laminin-1 or with a laminin-soluble peptide fragment [38]; a similar substrate-dependent response was observed for the membrane-bound chemotropic protein ephrin A-5 in RGC of Xenopus; a repulsive response was observed when cells were grown on fibronectin, while a response of attraction was exerted when cells grew over laminin [91]. The induction of neurite outgrowth in DRG neurons by nerve growth factor (NGF) and neurotrophin-3 (NT3) is inhibited when aggrecan or aggregates of aggrecan and hyaluronan are present [92], indicating that ECM component can also modify neurite response to secreted trophic factors. Cross-talk among ECM receptors, chemotropic proteins, and neurotrophin receptors has been well documented, for example, the proper innervation of sensory DRG seems to be

Cell-Cell and Cell-Matrix Interactions during Axons Guidance DOI: http://dx.doi.org/10.5772/intechopen.79681

calcium-dependent cadherins family, N-cadherin [20, 79]. The regulation of axons fasciculation could be exerted by modifying CAM expression or by modifying CAM interactions by post-translational modifications, as the addition of polysialic acid to NCAM (PSA-NCAM) [80]. Enhancement of axonal outgrowth has been previously shown by culturing neurons over transfected fibroblast expressing NCAM, Ncadherin, or L1 [81–83], allowing homophilic interactions of CAM expressed in fibroblasts and axon. CAMs also establish heterophilic interactions among proteins as integrin β1 [84], and receptors of chemotropic proteins as the ephrin receptors, EphA3, EphA4 [85], or semaphorins receptor, neuropilin-1 (Npn-1) with L1 [86], or EphA7 receptor with CHL1 [85], modulating the response to chemotropic proteins but also their adhesion. It has been shown that Npn-1, a receptor for class 3

semaphorins, is involved in the fasciculation of motor and sensory axons during limb innervation, and the selective depletion of Npn-1 in dorsal root ganglion neurons leads to defasciculation of motor projections, even when motor neurons still express Npn1, resulting in dorso-ventral incorrect targeting of motor neurons [87]. Npn-1 depletion also affects fasciculation and targeting of cranial nerves and Schwann cells migration [87]. Interestingly, altered projections of descending GAD65-positive fascicles from the MTG tract, present in double knockout mice for Slit chemotropic protein receptors Robo1/2, modify the nigrostriatal projection (NP) of dopaminergic neurons, impairing both tracts interactions, probably by the absence of homophilic Robo-Robo interactions and heterophilic interaction with NCAM proteins [88], explaining some of the Slit1/2 independent role of Robo-expressing axons during NP projection [89]. These results show that besides their role of mediating attraction or repulsive responses, some receptors for chemotropic proteins also mediate axons fasciculation by homo- and heterophilic interactions, and this role could be concealed or dismissed by the more characterized chemotropic response. Moreover, the absence of the expression of receptors Npn-1 and 2 in some of the DA axons projecting to the striatum and driven by semaphorins during NP formation suggests that fasciculation could be a relevant mechanism of guidance for these axons, and a complementary strategy for the projection of DA axons in addition to the chemotropic response [90].

As mentioned before, chemotropic proteins, extracellular matrices, and axon fasciculation are the main guidance cues during axon projection, their effects and mechanisms of action had been mainly studied as a separated stimulus by in vitro assays in explants or cell cultures, or in knockout animals; however, the panorama of axon projection during CNS formation implies simultaneous guidance cues, and projecting neurons should be responding and adapting according to all of them. Interactions among ECM with secreted chemotropic factors can modify their effects on axon projection, for example, it has been shown that the attraction response of RGC to chemotropic protein netrin-1 can be modified to repulsion after neurons interact with laminin-1 or with a laminin-soluble peptide fragment [38]; a similar substrate-dependent response was observed for the membrane-bound chemotropic protein ephrin A-5 in RGC of Xenopus; a repulsive response was observed when cells were grown on fibronectin, while a response of attraction was exerted when cells grew over laminin [91]. The induction of neurite outgrowth in DRG neurons by nerve growth factor (NGF) and neurotrophin-3 (NT3) is inhibited when aggrecan or aggregates of aggrecan and hyaluronan are present [92], indicating that ECM component can also modify neurite response to secreted trophic factors. Cross-talk among ECM receptors, chemotropic proteins, and neurotrophin receptors has been well documented, for example, the proper innervation of sensory DRG seems to be

3. Synergic effects of guidance cues

Neurons - Dendrites and Axons

8

dependent on the integrin expression, since a differential expression of α7 integrin in the subpopulations of DRG determines their response to NGF and NT-3 neurotrophin [93]. Semaphorin 3D, a repulsive chemotropic protein, can regulate MLF axons fasciculation by regulating the expression of L1 CAM in zebrafish, suggesting that besides the reported repulsive effects of semaphorins, their action could be exerted by the regulating expression of cell adhesion molecules [32]. Moreover, a complex interrelation among ECM, response to neurotropic factors, and cell-cell interactions has been reported for chick embryo DRG axons from in vitro explants cultured over a bioactive substrate; the NGF-induced outgrowth of DRG axons and Schwann cells from tissue explants was dependent on the density of the Arg-Gly-Asp (RGD) integrin-binding domain of fibronectin, and this effect was mediated by the upregulation of L1 and NCAM proteins by NGF that allowed the interactions among DRG neurons and Schwann cells [94].

#### 4. Guidance cues during regeneration

The generated knowledge about guidance cues as chemotropic proteins and ECM in axon guidance has led to multiple approaches to use them into the regeneration of CNS [95–97]. When the axonal continuity is interrupted by an injury or a disease, a correct axonal regeneration is required to effectively restore the nerve; in this process, cells and ECM interactions, chemotropic proteins, and factors as substrate stiffness are important. In vitro use of ECM as fibronectin has shown to support mouse cortical and hippocampal neurons axonal outgrowth mediated by α5β1 integrin [98]; in vivo application of fibrin/fibronectin gel at the rat spinal cord injury site is permissive to axonal outgrowth [99], and when fibrin glue is applied as a microsurgery suture at a sciatic nerve transplantation model in mouse, axons were more branched and travel longer distances reducing the regeneration time [100]. In the area of biomaterials engineering for axonal regeneration, several approaches promote neural outgrowth, combining ECM components and neurotrophic factors as laminin plus microspheres with neural growth factor and neurotrophin-3 for the repair of sciatic nerve in rats [101], or carbon-coated microfibers plus basic fibroblast growth factor and fibronectin for spinal cord injury [102]; moreover, the integration of stiffness, porosity, and adhesion promotion shows that an approach considering multiple factors can help to promote and orient axon outgrowth [103], and a soft and aligned fibrillary fibrin hydrogel promotes and directs axonal projection in a spinal cord injury in mouse [104]. The big challenge therefore is to integrate several cues to obtain a better and controlled growth cone response; the desired response could be obtained by developing biocompatible materials that allow an adequate scaffold containing both the chemical and physical cues, to allow an effective neural regeneration.

#### Acknowledgements

V-A. A. is a student of the Health Science Ph. D. program of the Universidad Veracruzana and receive the CONACYT scholarship number 297485. The authors acknowledge the Universidad Veracruzana Health Science Ph. D. program and the Educational Council Program PRODEP for their financial support.

#### Conflict of interest

The authors declare no conflict of interest.

Neurons - Dendrites and Axons

#### Author details

Vela-Alcántara Ana and Tamariz Elisa\* Health Science Institute, Universidad Veracruzana, Xalapa, Veracruz, México References

[1] Purves D, Augustine GJ, Fitzpatrick D, Hall WC, La-Mantia AS, McNamara JO. Neuroscience. 3rd ed. Sunderlan, MA, USA: Sinauer Associates; 2004

DOI: http://dx.doi.org/10.5772/intechopen.79681

Cell-Cell and Cell-Matrix Interactions during Axons Guidance

[9] Suter DM, Miller KE. The emerging role of forces in axonal elongation. Progress in Neurobiology. 2011;94(2):

[10] Gallo G, Letourneau PC. Regulation of growth cone actin filaments by guidance cues. Journal of Neurobiology.

[11] Lin CH, Forscher P. Growth cone advance is inversely proportional to retrograde F-actin flow. Neuron. 1995;

[12] Sabry JH, O'Connor TP, Evans L, Toroian-Raymond A, Kirschner M, Bentley D. Microtubule behavior during guidance of pioneer neuron growth cones in situ. The Journal of Cell Biology. 1991;115(2):381-395

[13] Myers JP, Gomez TM. Focal adhesion kinase promotes integrin adhesion dynamics necessary for chemotropic turning of nerve growth cones. The Journal of Neuroscience.

[14] Zaidel-Bar R, Itzkovitz S, Ma'ayan A, Iyengar R, Geiger B. Functional atlas of the integrin adhesome. Nature Cell

[15] Ciobanasu C, Faivre B, Le Clainche C.

2011;31(38):13585-13595

Biology. 2007;9(8):858-867

Integrating actin dynamics, mechanotransduction and integrin activation: The multiple functions of actin binding proteins in focal adhesions. European Journal of Cell Biology. 2013;92(10–11):339-348

[16] Robles E, Gomez TM. Focal adhesion kinase signaling at sites of integrin-mediated adhesion controls axon pathfinding. Nature Neuroscience.

TM. Cell adhesion and invasion

[17] Short CA, Suarez-Zayas EA, Gomez

2006;9(10):1274-1283

91-101

2004;58(1):92-102

14(4):763-771

Letourneau PC. Actin filament bundles

[3] Coles CH, Bradke F. Coordinating neuronal actin-microtubule dynamics. Current Biology. 2015;25(15):R677-R691

[4] Lowery LA, Van Vactor D. The trip of the tip: Understanding the growth cone machinery. Nature Reviews. Molecular Cell Biology. 2009;10(5):

[5] Suter DM, Forscher P. Substratecytoskeletal coupling as a mechanism for the regulation of growth cone motility and guidance. Journal of Neurobiology. 2000;44(2):97-113

[6] Letourneau PC, Shattuck TA, Ressler AH. "Pull" and "push" in neurite elongation: Observations on the effects of different concentrations of cytochalasin B and taxol. Cell Motility and the Cytoskeleton. 1987;

[7] Lee CW, Vitriol EA, Shim S, Wise AL, Velayutham RP, Zheng JQ.

Dynamic localization of G-actin during membrane protrusion in neuronal motility. Current Biology. 2013;23(12):

Semaphorin-mediated axonal guidance via Rho-related G proteins. Current Opinion in Cell Biology. 2001;13(5):

[8] Liu BP, Strittmatter SM.

[2] Challacombe JF, Snow DM,

are required for microtubule reorientation during growth cone turning to avoid an inhibitory guidance cue. Journal of Cell Science. 1996;109

(Pt 8):2031-2040

332-343

8(3):193-209

1046-1056

619-626

11

\*Address all correspondence to: etamariz@uv.mx

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Cell-Cell and Cell-Matrix Interactions during Axons Guidance DOI: http://dx.doi.org/10.5772/intechopen.79681

#### References

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[10] Gallo G, Letourneau PC. Regulation of growth cone actin filaments by guidance cues. Journal of Neurobiology. 2004;58(1):92-102

[11] Lin CH, Forscher P. Growth cone advance is inversely proportional to retrograde F-actin flow. Neuron. 1995; 14(4):763-771

[12] Sabry JH, O'Connor TP, Evans L, Toroian-Raymond A, Kirschner M, Bentley D. Microtubule behavior during guidance of pioneer neuron growth cones in situ. The Journal of Cell Biology. 1991;115(2):381-395

[13] Myers JP, Gomez TM. Focal adhesion kinase promotes integrin adhesion dynamics necessary for chemotropic turning of nerve growth cones. The Journal of Neuroscience. 2011;31(38):13585-13595

[14] Zaidel-Bar R, Itzkovitz S, Ma'ayan A, Iyengar R, Geiger B. Functional atlas of the integrin adhesome. Nature Cell Biology. 2007;9(8):858-867

[15] Ciobanasu C, Faivre B, Le Clainche C. Integrating actin dynamics, mechanotransduction and integrin activation: The multiple functions of actin binding proteins in focal adhesions. European Journal of Cell Biology. 2013;92(10–11):339-348

[16] Robles E, Gomez TM. Focal adhesion kinase signaling at sites of integrin-mediated adhesion controls axon pathfinding. Nature Neuroscience. 2006;9(10):1274-1283

[17] Short CA, Suarez-Zayas EA, Gomez TM. Cell adhesion and invasion

Author details

Neurons - Dendrites and Axons

10

Vela-Alcántara Ana and Tamariz Elisa\*

provided the original work is properly cited.

\*Address all correspondence to: etamariz@uv.mx

Health Science Institute, Universidad Veracruzana, Xalapa, Veracruz, México

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

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Cell-Cell and Cell-Matrix Interactions during Axons Guidance DOI: http://dx.doi.org/10.5772/intechopen.79681

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aligned collagen fibrils in vitro. Experimental Cell Research. 1976;98(1): 159-169

sufficient to promote neurite outgrowth. The Journal of Biological Chemistry. 1998;273(43):28444-28453

Neurons - Dendrites and Axons

[52] Faissner A, Clement A, Lochter A, Streit A, Mandl C, Schachner M. Isolation of a neural chondroitin sulfate proteoglycan with neurite outgrowth promoting properties. The Journal of Cell Biology. 1994;126(3):783-799

[59] Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell.

[60] Flanagan LA, Ju YE, Marg B, Osterfield M, Janmey PA. Neurite branching on deformable substrates. Neuroreport. 2002;13(18):2411-2415

[61] Moore SW, Sheetz MP. Biophysics of substrate interaction: Influence on neural motility, differentiation, and repair. Developmental Neurobiology.

[62] Iwashita M, Kataoka N, Toida K, Kosodo Y. Systematic profiling of spatiotemporal tissue and cellular stiffness in the developing brain. Development. 2014;141(19):3793-3798

[63] Koser DE, Thompson AJ, Foster SK, Dwivedy A, Pillai EK, Sheridan GK, et al. Mechanosensing is critical for axon growth in the developing brain. Nature Neuroscience. 2016;19(12):1592-1598

[64] Campbell DS, Regan AG, Lopez JS, Tannahill D, Harris WA, Holt CE. Semaphorin 3A elicits stage-dependent collapse, turning, and branching in Xenopus retinal growth cones. The Journal of Neuroscience. 2001;21(21):

[65] Piper M, Anderson R, Dwivedy A, Weinl C, van Horck F, Leung KM, et al. Signaling mechanisms underlying Slit2 induced collapse of Xenopus retinal growth cones. Neuron. 2006;49(2):

[66] Moeendarbary E, Weber IP, Sheridan GK, Koser DE, Soleman S, Haenzi B, et al. The soft mechanical signature of glial scars in the central

[67] Ebendal T. The relative roles of contact inhibition and contact guidance in orientation of axons extending on

nervous system. Nature Communications. 2017;8:14787

2006;126(4):677-689

2011;71(11):1090-1101

8538-8547

215-228

[53] Ring C, Lemmon V, Halfter W. Two chondroitin sulfate proteoglycans

[54] Snow DM, Brown EM, Letourneau PC. Growth cone behavior in the presence of soluble chondroitin sulfate proteoglycan (CSPG), compared to behavior on CSPG bound to laminin or fibronectin. International Journal of Developmental Neuroscience. 1996;

[55] Snow DM, Smith JD, Cunningham AT, McFarlin J, Goshorn EC. Neurite elongation on chondroitin sulfate proteoglycans is characterized by axonal fasciculation. Experimental Neurology.

[56] Discher DE, Janmey P, Wang YL. Tissue cells feel and respond to the stiffness of their substrate. Science.

[57] Georges PC, Miller WJ, Meaney DF, Sawyer ES, Janmey PA. Matrices with compliance comparable to that of brain tissue select neuronal over glial growth in mixed cortical cultures. Biophysical Journal. 2006;90(8):3012-3018

[58] Moore SW, Roca-Cusachs P, Sheetz MP. Stretchy proteins on stretchy substrates: The important elements of integrin-mediated rigidity sensing. Developmental Cell. 2010;19(2):

differentially expressed in the developing chick visual system. Developmental Biology. 1995;168(1):

11-27

14(3):331-349

2003;182(2):310-321

2005;310(5751):1139-1143

194-206

14

[68] Simitzi C, Ranella A, Stratakis E. Controlling the morphology and outgrowth of nerve and neuroglial cells: The effect of surface topography. Acta Biomaterialia. 2017;51:21-52

[69] Binder C, Milleret V, Hall H, Eberli D, Luhmann T. Influence of micro and submicro poly(lactic-glycolic acid) fibers on sensory neural cell locomotion and neurite growth. Journal of Biomedical Materials Research. Part B, Applied Biomaterials. 2013;101(7): 1200-1208

[70] Gnavi S, Morano M, Fornasari BE, Riccobono C, Tonda-Turo C, Zanetti M, et al. Combined influence of gelatin fibre topography and growth factors on cultured dorsal root ganglia neurons. The Anatomical Record. 2018. [Epub ahead of print]

[71] Wilson SW, Ross LS, Parrett T, Easter SS Jr. The development of a simple scaffold of axon tracts in the brain of the embryonic zebrafish, Brachydanio rerio. Development (Cambridge, England). 1990;108(1): 121-145

[72] Ware M, Dupe V, Schubert FR. Evolutionary conservation of the early axon scaffold in the vertebrate brain. Developmental Dynamics. 2015; 244(10):1202-1214

[73] Mastick GS, Easter SS Jr. Initial organization of neurons and tracts in the embryonic mouse fore- and midbrain. Developmental Biology. 1996;173(1):79-94

[74] Raper JA, Bastiani M, Goodman CS. Pathfinding by neuronal growth cones in grasshopper embryos. II. Selective fasciculation onto specific axonal pathways. The Journal of Neuroscience. 1983;3(1):31-41

[75] Grenningloh G, Goodman CS. Pathway recognition by neuronal growth cones: Genetic analysis of neural cell adhesion molecules in Drosophila. Current Opinion in Neurobiology. 1992; 2(1):42-47

[76] Pollerberg GE, Thelen K, Theiss MO, Hochlehnert BC. The role of cell adhesion molecules for navigating axons: Density matters. Mechanisms of Development. 2013;130(6–8):359-372

[77] Bak M, Fraser SE. Axon fasciculation and differences in midline kinetics between pioneer and follower axons within commissural fascicles. Development (Cambridge, England). 2003;130(20):4999-5008

[78] Pike SH, Melancon EF, Eisen JS. Pathfinding by zebrafish motoneurons in the absence of normal pioneer axons. Development (Cambridge, England). 1992;114(4):825-831

[79] Sakurai T. The role of cell adhesion molecules in brain wiring and neuropsychiatric disorders. Molecular and Cellular Neurosciences. 2017;81: 4-11

[80] Wakade CG, Mehta SH, Maeda M, Webb RC, Chiu FC. Axonal fasciculation and the role of polysialic acid-neural cell adhesion molecule in rat cortical neurons. Journal of Neuroscience Research. 2013;91(11): 1408-1418

[81] Doherty P, Barton CH, Dickson G, Seaton P, Rowett LH, Moore SE, et al. Neuronal process outgrowth of human sensory neurons on monolayers of cells transfected with cDNAs for five human N-CAM isoforms. The Journal of Cell Biology. 1989;109(2):789-798

[82] Doherty P, Rowett LH, Moore SE, Mann DA, Walsh FS. Neurite outgrowth in response to transfected N-CAM and N-cadherin reveals fundamental

differences in neuronal responsiveness to CAMs. Neuron. 1991;6(2):247-258

[83] Williams EJ, Doherty P, Turner G, Reid RA, Hemperly JJ, Walsh FS. Calcium influx into neurons can solely account for cell contact-dependent neurite outgrowth stimulated by transfected L1. The Journal of Cell Biology. 1992;119(4):883-892

[84] Silletti S, Mei F, Sheppard D, Montgomery AM. Plasmin-sensitive dibasic sequences in the third fibronectin-like domain of L1-cell adhesion molecule (CAM) facilitate homomultimerization and concomitant integrin recruitment. The Journal of Cell Biology. 2000;149(7):1485-1502

[85] Demyanenko GP, Siesser PF, Wright AG, Brennaman LH, Bartsch U, Schachner M, et al. L1 and CHL1 cooperate in thalamocortical axon targeting. Cerebral Cortex. 2011;21(2): 401-412

[86] Castellani V, De Angelis E, Kenwrick S, Rougon G. Cis and trans interactions of L1 with neuropilin-1 control axonal responses to semaphorin 3A. The EMBO Journal. 2002;21(23): 6348-6357

[87] Huettl RE, Huber AB. Cranial nerve fasciculation and Schwann cell migration are impaired after loss of Npn-1. Developmental Biology. 2011; 359(2):230-241

[88] Garcia-Pena CM, Kim M, Frade-Perez D, Avila-Gonzalez D, Tellez E, Mastick GS, et al. Ascending midbrain dopaminergic axons require descending GAD65 axon fascicles for normal pathfinding. Frontiers in Neuroanatomy. 2014;8:43

[89] Dugan JP, Stratton A, Riley HP, Farmer WT, Mastick GS. Midbrain dopaminergic axons are guided longitudinally through the diencephalon by Slit/Robo signals.

Molecular and Cellular Neurosciences. 2011;46(1):347-356

[97] Volpato FZ, Fuhrmann T, Migliaresi C, Hutmacher DW, Dalton PD. Using extracellular matrix for regenerative

DOI: http://dx.doi.org/10.5772/intechopen.79681

Cell-Cell and Cell-Matrix Interactions during Axons Guidance

elasticity and aligned topography on stem cell neurogenic differentiation and rapid neurite outgrowth. Nanoscale.

2016;8(19):10252-10265

Biomaterials. 2013;34(21):4945-4955

[98] Tonge DA, de Burgh HT, Docherty R, Humphries MJ, Craig SE, Pizzey J. Fibronectin supports neurite outgrowth and axonal regeneration of adult brain neurons in vitro. Brain Research. 2012;

[99] King VR, Alovskaya A, Wei DYT, Brown RA, Priestley JV. The use of injectable forms of fibrin and

fibronectin to support axonal ingrowth after spinal cord injury. Biomaterials.

[100] Koulaxouzidis G, Reim G, Witzel C. Fibrin glue repair leads to enhanced axonal elongation during early peripheral nerve regeneration in an in vivo mouse model. Neural Regeneration Research. 2015;10(7):

[101] Santos D, Gonzalez-Perez F, Giudetti G, Micera S, Udina E, Del Valle J, et al. Preferential enhancement of sensory and motor axon regeneration by combining extracellular matrix components with neurotrophic factors. International Journal of Molecular Sciences. 2016;18(1)

[102] Alves-Sampaio A, Garcia-Rama C, Collazos-Castro JE. Biofunctionalized PEDOT-coated microfibers for the treatment of spinal cord injury. Biomaterials. 2016;89:98-113

[103] Kubinova S, Horak D, Hejcl A, Plichta Z, Kotek J, Proks V, et al. SIKVAV-modified highly superporous PHEMA scaffolds with oriented pores for spinal cord injury repair. Journal of Tissue Engineering and Regenerative Medicine. 2015;9(11):1298-1309

[104] Yao S, Liu X, Yu S, Wang X, Zhang S, Wu Q, et al. Co-effects of matrix low

2010;31(15):4447-4456

medicine in the spinal cord.

1453:8-16

1166-1171

17

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[91] Weinl C, Drescher U, Lang S, Bonhoeffer F, Loschinger J. On the turning of Xenopus retinal axons induced by ephrin-A5. Development. 2003;130(8):1635-1643

[92] Chan CC, Roberts CR, Steeves JD, Tetzlaff W. Aggrecan components differentially modulate nerve growth factor-responsive and neurotrophin-3 responsive dorsal root ganglion neurite growth. Journal of Neuroscience Research. 2008;86(3):581-592

[93] Gardiner NJ, Fernyhough P, Tomlinson DR, Mayer U, von der Mark H, Streuli CH. Alpha7 integrin mediates neurite outgrowth of distinct populations of adult sensory neurons. Molecular and Cellular Neurosciences. 2005;28(2):229-240

[94] Romano NH, Madl CM, Heilshorn SC. Matrix RGD ligand density and L1CAM-mediated Schwann cell interactions synergistically enhance neurite outgrowth. Acta Biomaterialia. 2015;11:48-57

[95] Giger RJ, Hollis ER 2nd, Tuszynski MH. Guidance molecules in axon regeneration. Cold Spring Harbor Perspectives in Biology. 2010;2(7): a001867

[96] McCall J, Weidner N, Blesch A. Neurotrophic factors in combinatorial approaches for spinal cord regeneration. Cell and Tissue Research. 2012;349(1): 27-37

Cell-Cell and Cell-Matrix Interactions during Axons Guidance DOI: http://dx.doi.org/10.5772/intechopen.79681

[97] Volpato FZ, Fuhrmann T, Migliaresi C, Hutmacher DW, Dalton PD. Using extracellular matrix for regenerative medicine in the spinal cord. Biomaterials. 2013;34(21):4945-4955

differences in neuronal responsiveness to CAMs. Neuron. 1991;6(2):247-258

Neurons - Dendrites and Axons

Molecular and Cellular Neurosciences.

[90] Hernandez-Montiel HL, Tamariz E,

Echavarria A. Semaphorins 3A, 3C, and 3F in mesencephalic dopaminergic axon

Comparative Neurology. 2008;506(3):

[92] Chan CC, Roberts CR, Steeves JD, Tetzlaff W. Aggrecan components differentially modulate nerve growth factor-responsive and neurotrophin-3 responsive dorsal root ganglion neurite growth. Journal of Neuroscience Research. 2008;86(3):581-592

[93] Gardiner NJ, Fernyhough P, Tomlinson DR, Mayer U, von der Mark H, Streuli CH. Alpha7 integrin mediates

neurite outgrowth of distinct

2005;28(2):229-240

2015;11:48-57

a001867

27-37

populations of adult sensory neurons. Molecular and Cellular Neurosciences.

[94] Romano NH, Madl CM, Heilshorn SC. Matrix RGD ligand density and L1CAM-mediated Schwann cell interactions synergistically enhance neurite outgrowth. Acta Biomaterialia.

[95] Giger RJ, Hollis ER 2nd, Tuszynski MH. Guidance molecules in axon regeneration. Cold Spring Harbor Perspectives in Biology. 2010;2(7):

[96] McCall J, Weidner N, Blesch A. Neurotrophic factors in combinatorial approaches for spinal cord regeneration. Cell and Tissue Research. 2012;349(1):

[91] Weinl C, Drescher U, Lang S, Bonhoeffer F, Loschinger J. On the turning of Xenopus retinal axons induced by ephrin-A5. Development.

Sandoval-Minero MT, Varela-

pathfinding. The Journal of

2003;130(8):1635-1643

2011;46(1):347-356

387-397

[83] Williams EJ, Doherty P, Turner G, Reid RA, Hemperly JJ, Walsh FS. Calcium influx into neurons can solely account for cell contact-dependent neurite outgrowth stimulated by transfected L1. The Journal of Cell Biology. 1992;119(4):883-892

[84] Silletti S, Mei F, Sheppard D, Montgomery AM. Plasmin-sensitive dibasic sequences in the third fibronectin-like domain of L1-cell adhesion molecule (CAM) facilitate homomultimerization and concomitant integrin recruitment. The Journal of Cell

Biology. 2000;149(7):1485-1502

[85] Demyanenko GP, Siesser PF, Wright AG, Brennaman LH, Bartsch U, Schachner M, et al. L1 and CHL1 cooperate in thalamocortical axon targeting. Cerebral Cortex. 2011;21(2):

[86] Castellani V, De Angelis E, Kenwrick S, Rougon G. Cis and trans interactions of L1 with neuropilin-1 control axonal responses to semaphorin 3A. The EMBO Journal. 2002;21(23):

fasciculation and Schwann cell migration are impaired after loss of Npn-1. Developmental Biology. 2011;

pathfinding. Frontiers in Neuroanatomy. 2014;8:43

[87] Huettl RE, Huber AB. Cranial nerve

[88] Garcia-Pena CM, Kim M, Frade-Perez D, Avila-Gonzalez D, Tellez E, Mastick GS, et al. Ascending midbrain dopaminergic axons require descending GAD65 axon fascicles for normal

[89] Dugan JP, Stratton A, Riley HP, Farmer WT, Mastick GS. Midbrain dopaminergic axons are guided longitudinally through the

diencephalon by Slit/Robo signals.

401-412

6348-6357

359(2):230-241

16

[98] Tonge DA, de Burgh HT, Docherty R, Humphries MJ, Craig SE, Pizzey J. Fibronectin supports neurite outgrowth and axonal regeneration of adult brain neurons in vitro. Brain Research. 2012; 1453:8-16

[99] King VR, Alovskaya A, Wei DYT, Brown RA, Priestley JV. The use of injectable forms of fibrin and fibronectin to support axonal ingrowth after spinal cord injury. Biomaterials. 2010;31(15):4447-4456

[100] Koulaxouzidis G, Reim G, Witzel C. Fibrin glue repair leads to enhanced axonal elongation during early peripheral nerve regeneration in an in vivo mouse model. Neural Regeneration Research. 2015;10(7): 1166-1171

[101] Santos D, Gonzalez-Perez F, Giudetti G, Micera S, Udina E, Del Valle J, et al. Preferential enhancement of sensory and motor axon regeneration by combining extracellular matrix components with neurotrophic factors. International Journal of Molecular Sciences. 2016;18(1)

[102] Alves-Sampaio A, Garcia-Rama C, Collazos-Castro JE. Biofunctionalized PEDOT-coated microfibers for the treatment of spinal cord injury. Biomaterials. 2016;89:98-113

[103] Kubinova S, Horak D, Hejcl A, Plichta Z, Kotek J, Proks V, et al. SIKVAV-modified highly superporous PHEMA scaffolds with oriented pores for spinal cord injury repair. Journal of Tissue Engineering and Regenerative Medicine. 2015;9(11):1298-1309

[104] Yao S, Liu X, Yu S, Wang X, Zhang S, Wu Q, et al. Co-effects of matrix low

elasticity and aligned topography on stem cell neurogenic differentiation and rapid neurite outgrowth. Nanoscale. 2016;8(19):10252-10265

**19**

Section 2

Neurons and

Neurodegenerative

Disease

Section 2

Neurons and Neurodegenerative Disease

**21**

**Chapter 2**

**Abstract**

no current cure.

neurodegeneration

**1. Introduction**

Roles of Semaphorins in

Neurodegenerative Diseases

*María Elsa Pando and María Antonieta Valenzuela*

**Keywords:** semaphorin, neuropilin, plexin, neuroimmune cross talk,

Semaphorins (Sema) are a large family of proteins originally discovered as axon guidance signals during development as signals toward proper innervation of targets [1]. Semaphorin function is fundamental during embryonic development, yet they are also largely expressed in the adult brain. In the past decades, an increasing amount of evidence shows that semaphorins participate in refining synaptogenesis, dendritic and axonal exuberance, remodeling of the synaptic network, and even modulating neuronal response to reactive oxygen species and neuronal apoptosis. The association of semaphorins to neuronal function and cell death was soon explored in the context of neurological diseases [2–6]. Several reports linking alteration of semaphorin function or expression in neuropathologies opened an unexplored door to understand the mechanisms and look for treatment alternatives

*Sebastian Quintremil, Fernando Medina Ferrer, Javier Puente,* 

Semaphorins are secreted and transmembrane proteins that bind plexin/ neuropilin or integrin receptors, providing paracrine axonal guidance signals and ultimately leading to a functional and developed neuronal network. Following semaphorin's initial discovery, their relevance in the central nervous system (CNS) soon intrigued researchers about the possible links between semaphorins, their receptors and signaling mechanisms and different neurodegenerative diseases. Here, we explore the current knowledge of semaphorin's function and signaling in Alzheimer's disease (AD), Parkinson's disease (PD), Charcot-Marie-Tooth disease (CMT), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We focus on the effects of the most known semaphorin subclasses 3A and 4D, yet extending our discussion to other semaphorins that have been found involved in specific neuropathologies and the potential effect of semaphorins modulating the immune system in disorders with inflammatory components. Molecular, cellular, and genetic evidences are reviewed, highlighting the relevance of semaphorins on each disease etiology, pathophysiology, and progression. The newly discovered semaphorin functions in neurological disorders even suggest alternative therapies that may be highly valuable in diseases that have

#### **Chapter 2**

## Roles of Semaphorins in Neurodegenerative Diseases

*Sebastian Quintremil, Fernando Medina Ferrer, Javier Puente, María Elsa Pando and María Antonieta Valenzuela*

#### **Abstract**

Semaphorins are secreted and transmembrane proteins that bind plexin/ neuropilin or integrin receptors, providing paracrine axonal guidance signals and ultimately leading to a functional and developed neuronal network. Following semaphorin's initial discovery, their relevance in the central nervous system (CNS) soon intrigued researchers about the possible links between semaphorins, their receptors and signaling mechanisms and different neurodegenerative diseases. Here, we explore the current knowledge of semaphorin's function and signaling in Alzheimer's disease (AD), Parkinson's disease (PD), Charcot-Marie-Tooth disease (CMT), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We focus on the effects of the most known semaphorin subclasses 3A and 4D, yet extending our discussion to other semaphorins that have been found involved in specific neuropathologies and the potential effect of semaphorins modulating the immune system in disorders with inflammatory components. Molecular, cellular, and genetic evidences are reviewed, highlighting the relevance of semaphorins on each disease etiology, pathophysiology, and progression. The newly discovered semaphorin functions in neurological disorders even suggest alternative therapies that may be highly valuable in diseases that have no current cure.

**Keywords:** semaphorin, neuropilin, plexin, neuroimmune cross talk, neurodegeneration

#### **1. Introduction**

Semaphorins (Sema) are a large family of proteins originally discovered as axon guidance signals during development as signals toward proper innervation of targets [1]. Semaphorin function is fundamental during embryonic development, yet they are also largely expressed in the adult brain. In the past decades, an increasing amount of evidence shows that semaphorins participate in refining synaptogenesis, dendritic and axonal exuberance, remodeling of the synaptic network, and even modulating neuronal response to reactive oxygen species and neuronal apoptosis. The association of semaphorins to neuronal function and cell death was soon explored in the context of neurological diseases [2–6]. Several reports linking alteration of semaphorin function or expression in neuropathologies opened an unexplored door to understand the mechanisms and look for treatment alternatives of disorders with unknown or poorly understood pathological origins. Here, we aim to summarize the state of the art involving semaphorins on Alzheimer's disease (AD), Parkinson's disease (PD), Charcot-Marie-tooth disease (CMT), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/ TSP caused by HTLV-1 infection).

The role of semaphorins in neurological diseases depends on the different types of semaphorins, their receptors, different signaling pathways they activate, and the neuronal context [1]. For instance, some semaphorins are considered axon repellent in a particular neuronal context/disease, while chemoattractant in others. Similarly, some semaphorins are toxic to neurons and promote apoptosis, while others are neuroprotective. The bifunctionality of semaphorins is mirrored in a myriad of neurological affections and, therefore we, by no means, attempt to provide the reader with a complete list of diseases affected by Sema signaling or a thorough understanding of the Sema family members, their receptor, and their signaling pathways (refer to [2] instead), but rather provide an introductory reading for understanding semaphorin function in neurological pathologies.

#### **1.1 Neurological disorders and the common factor of semaphorin**

Neurological disorders of the central nervous system (CNS) are diseases with structural, biochemical, or electrical abnormalities in the brain and spinal cord caused by gene mutations, neuron damage, dysfunction of axon-dendrite connections, myelin loss, and/or damage of the surrounding vascular system. Neurological disorders include AD, PD, CMT, and ALS, sometimes showing an important immune component as MS and HAM/TSP [7, 8]. Currently, semaphorins are related with health and disease in the cardiovascular, immune, and central nervous systems. Although neurological disorders have different pathological origins, the participation of Sema signaling is a common factor [1, 9, 10]. Activation of semaphorin receptors in the neuronal growth cone promotes changes of cytoskeletal dynamics, resulting in an axon extension alteration and therefore possible neuronal dysfunctions in the context of neuropathologies [1, 11].

#### **2. Semaphorin signaling**

Semaphorins are a family of eight different subclasses with several members each, grouped based on amino acid sequence and structural similarities. Semaphorins include secreted and membrane-bound glycoproteins that bind mainly to plexin receptors (most relevant semaphorins related with neurological disorders are summarized in **Table 1**) [1, 2]. Plexins (PLXN) are a family of nine types of transmembrane semaphorin receptors (plexins A1, A2, A3, A4, B1, B2, B3, C1, and D1). Class 3 semaphorins bind to neuropilins (NRP1 and NRP2) that act as co-receptors forming an heterocomplex with type A plexins (the transducing unit), and in some cases, the Sema3-plexinneuropilin complex may also associate with cell adhesion molecules of the IgCAM superfamily. Class 7 semaphorins bind to integrin receptors instead of plexins and neuropilins [1–3, 11–15]. While plexins seem to act as receptors for semaphorins only, the cell surface NRP receptors have pleiotropic functions, being also co-receptors for vascular endothelial growth factor (VEGF). NRP1 has high affinity for VEGF-A and is required for signal transduction after association to the VEGF receptor [16, 17]. Competition between VEGF and Sema3A for partially overlapping binding sites on NRP1 may produce a signaling unbalance potentially involved in neuropathologies.

**23**

axon retraction and growth cone collapse [21, 22].

*Roles of Semaphorins in Neurodegenerative Diseases DOI: http://dx.doi.org/10.5772/intechopen.82046*

Sema2A CMT Plexin B

AD, PD, ALS, MS

MS, HAM/ TSP

Sema5A AD, PD, Plexin B3/Nrp2, CSPGs,

Sema7A PD, MS b1-integrins, α,b-

HSPGs, TK

integrins, plexin C1

*Receptors [1, 2, 10, 12, 15], cell expression [9, 10] functions [9], and diseases discussed here are indicated.*

Sema3A Sema3B Sema3C Sema3D Sema3E Sema3F

Sema4A Sema4D

**Table 1.**

*Semaphorins in neurological diseases.*

**Sema Disease Receptors/coreceptors Cell** 

Sema1A

Plexin A1-4/Nrp1/Nrp2, IgCAM, RTK, integrins, proteoglycans VEGFR2

Plexin B1/Met, ErbB2, Timp2, RTK

**expression**

Neurons, glia, immune cells

Neurons, glia, immune cells, endothelial cells, thymus

Neurons, glia, immune cells, fibroblasts, thymus

**Functions**

Neurons Neuronal connectivity, cell migration

responses

Neurons, glia Cytoskeletal organization,

patterning

Cytoskeletal organization, cell migration, cell adhesion, immunomodulation, stimulating cytokine production,

Cytoskeletal organization, neuronal connectivity, regeneration, synaptic transmission, regeneration, cell migration, angiogenesis, immune responses

Cytoskeletal organization, neuronal connectivity, angiogenesis, cell migration, synaptic transmission, regeneration, immune

neuronal connectivity, synaptogenesis, vascular

proinflammatory responses

Once semaphorins bind to their receptors, the transducing unit triggers signaling pathways linking several protein kinases and downstream substrates that overall change microtubule and actin dynamics, promoting growth cone collapse and axon repulsion in neurons. Nevertheless, changes in the neuronal environment or the type of semaphorin/receptor complex may shape a different transduction effect. Plexin receptors contain a cytoplasmic region acting as a GTPase-activating protein to bind and stimulate GTPase activity of Rho, Rac1, Rnd1, and R-Ras proteins. For instance, the G-protein R-Ras is involved in neuronal sprouting and cell adhesion via activation of integrins. Semaphorin signaling via plexin A1/B1 inactivates R-Ras. Sema3A- and Sema4D-mediated signaling, therefore, inhibit integrin β1 subunits through downregulation of R-Ras, leading to a reduction of growth cone adhesion and allowing collapse responses [1, 2, 10, 15]. Another central protein participating in semaphorin-induced growth cone collapse signaling is collapsin response mediator protein-2 (CRMP-2). CRMP-2 is a phosphoprotein mostly expressed in the CNS and involved in the cytoskeleton structure and function of neuronal cells through the induction of microtubule dynamics/assembly by binding to α- and β-tubulin heterodimers. The complex CRMP-2/kinesin-1 regulates soluble tubulin transport to the distal part of the growing axon and also neurite formation by modulating tubulin GTPase via intramolecular interaction with its N-terminal inhibitory region [18–20]. The affinity of CRMP-2 for tubulin is significantly diminished when specific residues are phosphorylated, leading to


*Roles of Semaphorins in Neurodegenerative Diseases DOI: http://dx.doi.org/10.5772/intechopen.82046*

**Table 1.**

*Neurons - Dendrites and Axons*

TSP caused by HTLV-1 infection).

of disorders with unknown or poorly understood pathological origins. Here, we aim to summarize the state of the art involving semaphorins on Alzheimer's disease (AD), Parkinson's disease (PD), Charcot-Marie-tooth disease (CMT), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/

The role of semaphorins in neurological diseases depends on the different types of semaphorins, their receptors, different signaling pathways they activate, and the neuronal context [1]. For instance, some semaphorins are considered axon repellent in a particular neuronal context/disease, while chemoattractant in others. Similarly, some semaphorins are toxic to neurons and promote apoptosis, while others are neuroprotective. The bifunctionality of semaphorins is mirrored in a myriad of neurological affections and, therefore we, by no means, attempt to provide the reader with a complete list of diseases affected by Sema signaling or a thorough understanding of the Sema family members, their receptor, and their signaling pathways (refer to [2] instead), but rather provide an introductory reading for

Neurological disorders of the central nervous system (CNS) are diseases with structural, biochemical, or electrical abnormalities in the brain and spinal cord caused by gene mutations, neuron damage, dysfunction of axon-dendrite connections, myelin loss, and/or damage of the surrounding vascular system. Neurological disorders include AD, PD, CMT, and ALS, sometimes showing an important immune component as MS and HAM/TSP [7, 8]. Currently, semaphorins are related with health and disease in the cardiovascular, immune, and central nervous systems. Although neurological disorders have different pathological origins, the participation of Sema signaling is a common factor [1, 9, 10]. Activation of semaphorin receptors in the neuronal growth cone promotes changes of cytoskeletal dynamics, resulting in an axon extension alteration and therefore possible neuronal

Semaphorins are a family of eight different subclasses with several members each,

grouped based on amino acid sequence and structural similarities. Semaphorins include secreted and membrane-bound glycoproteins that bind mainly to plexin receptors (most relevant semaphorins related with neurological disorders are summarized in **Table 1**) [1, 2]. Plexins (PLXN) are a family of nine types of transmembrane semaphorin receptors (plexins A1, A2, A3, A4, B1, B2, B3, C1, and D1). Class 3 semaphorins bind to neuropilins (NRP1 and NRP2) that act as co-receptors forming an heterocomplex with type A plexins (the transducing unit), and in some cases, the Sema3-plexinneuropilin complex may also associate with cell adhesion molecules of the IgCAM superfamily. Class 7 semaphorins bind to integrin receptors instead of plexins and neuropilins [1–3, 11–15]. While plexins seem to act as receptors for semaphorins only, the cell surface NRP receptors have pleiotropic functions, being also co-receptors for vascular endothelial growth factor (VEGF). NRP1 has high affinity for VEGF-A and is required for signal transduction after association to the VEGF receptor [16, 17]. Competition between VEGF and Sema3A for partially overlapping binding sites on NRP1 may produce a signaling unbalance potentially involved in neuropathologies.

understanding semaphorin function in neurological pathologies.

dysfunctions in the context of neuropathologies [1, 11].

**2. Semaphorin signaling**

**1.1 Neurological disorders and the common factor of semaphorin**

**22**

*Semaphorins in neurological diseases.*

Once semaphorins bind to their receptors, the transducing unit triggers signaling pathways linking several protein kinases and downstream substrates that overall change microtubule and actin dynamics, promoting growth cone collapse and axon repulsion in neurons. Nevertheless, changes in the neuronal environment or the type of semaphorin/receptor complex may shape a different transduction effect. Plexin receptors contain a cytoplasmic region acting as a GTPase-activating protein to bind and stimulate GTPase activity of Rho, Rac1, Rnd1, and R-Ras proteins. For instance, the G-protein R-Ras is involved in neuronal sprouting and cell adhesion via activation of integrins. Semaphorin signaling via plexin A1/B1 inactivates R-Ras. Sema3A- and Sema4D-mediated signaling, therefore, inhibit integrin β1 subunits through downregulation of R-Ras, leading to a reduction of growth cone adhesion and allowing collapse responses [1, 2, 10, 15]. Another central protein participating in semaphorin-induced growth cone collapse signaling is collapsin response mediator protein-2 (CRMP-2). CRMP-2 is a phosphoprotein mostly expressed in the CNS and involved in the cytoskeleton structure and function of neuronal cells through the induction of microtubule dynamics/assembly by binding to α- and β-tubulin heterodimers. The complex CRMP-2/kinesin-1 regulates soluble tubulin transport to the distal part of the growing axon and also neurite formation by modulating tubulin GTPase via intramolecular interaction with its N-terminal inhibitory region [18–20]. The affinity of CRMP-2 for tubulin is significantly diminished when specific residues are phosphorylated, leading to axon retraction and growth cone collapse [21, 22].

### **3. Semaphorin regulatory functions on neuronal and non-neuronal cells**

#### **3.1 Axonal degeneration associated to cytoskeleton organization**

The roles of Sema3A and Sema4D are to produce alteration of both actin and microtubule dynamics in the cytoskeleton organization (ratio of the polymerization/ depolymerization rates). The effects of Sema3A and Sema4D on actin dynamics include the downregulation of PI3K-Akt signaling pathway, inhibiting integrinmediated adhesion as well as repulsive effects on axonal growing associated to actin-rich structure loss of lamellipodia and filopodia as part of the cofilin pathway triggered by Sema3A, or activation of myosin II (MyoII) and F-actin bundles promoted by Sema4D-ROCK signaling [2, 23, 24]. Sema3A additionally mediates an increase of the nonphosphorylated active form of myosin II (MyoII) and decreases the phosphorylation levels of Ezrin, Radixin, and Moesin (ERM) proteins. The nonphosphorylated active form of MyoII promotes retraction, while low ERM phosphorylation reduces the crosslinking between actin filaments and the plasma membrane [2, 25, 26]. Regarding microtubule dynamics, Sema4D signaling induces the inactivation of CRMP-2 by glycogen synthase kinase 3 beta (GSK3B)-mediated phosphorylation, leading to reduced binding of CRMP-2 to tubulin and consequently limiting its stabilizing function at the plus end of microtubules. Sema3A induces a similar CRMP-2-inactivating mechanism, yet requiring phosphorylation by cyclindependent kinase 5 (Cdk5) at Ser522 and GSK3B at Thr509/514 [2, 21, 22].

#### **3.2 Axonal degeneration associated to synaptogenesis and synaptic plasticity**

Synapsis formation of the neuronal network requires local participation of cell adhesion molecules, extracellular proteins, and axon guidance molecules at axodendritic sites [6]. Sema3A and VEGF signaling have been proposed to actively modulate the synaptogenesis and synaptic plasticity, since they are dysregulated in neurological diseases, such as AD [4, 16, 17]. Proper regulation of the synapse formation and dendritic branching contributes to a normal balance between excitatory and inhibitory synaptic transmission; dysregulation of this balance would interfere with the regeneration of damaged CNS axons [6, 11, 15, 27, 28].

#### **3.3 Semaphorin function on axonal regeneration**

Models of axonal regeneration have been studied after spinal cord injury, which can produce a permanent damage because axonal growth and regeneration are limited after injury [29]. In adult mammals, some myelin proteins produced by myelinating oligodendrocytes, such as Nogo-A, MAG and OMgp, inhibit spinal cord regeneration [4]. Additionally, glial cells release chondroitin sulfate proteoglycans (CSPGs) and lecticans, such as neurocan, brevican, phosphacan, and tenascin to form the neuronal extracellular matrix (perineuronal nets). The perineuronal nets, together with other extracellular proteins, such as, ephrins, slits, netrins, bone morphogenic proteins, Wnts, and semaphorins are among the molecules most likely involved in limiting axonal regeneration [4, 30–33]. However, the function of semaphorins is dependent on the cellular context and may also favor axon regeneration. For instance, nerve growth factor (NGF) co-injected with Sema3A in trigeminal neuronal cell culture induced neuron regeneration [34]. Sema3A has also been implicated in the restoration of functionally motor innervation required to regenerate fibers [35]. Sema4D has shown enhanced locomotor recovery and axon regeneration when expressed in motoneurons, attributed to regulation of microglia function following spinal cord injury in adult zebrafish [36].

**25**

*Roles of Semaphorins in Neurodegenerative Diseases DOI: http://dx.doi.org/10.5772/intechopen.82046*

PI3K-Akt signaling pathway [37, 40].

**3.5 Semaphorin function on remyelination**

oligodendrocytes located near the injury site [9, 2, 45].

**3.6 Semaphorin function on immune responses**

**3.4 Semaphorin function on revascularization**

Revascularization (restoration of perfusion) is regulated by several growth factors secreted from endothelial cells, such as VEGFA, FGF, and PDGFs [4]. Class 3 semaphorins are considered anti-angiogenic semaphorins (e.g., Sema3A, Sema3E, and Sema3F), because they interfere with the effect of VEGF by competing for the same NRP receptor [37, 38]. Sema3A not only targets the actin cytoskeleton, but also the assembly/disassembly of focal adhesions, altering migration, proliferation, and adherence of endothelial cells [37]. Sema3A and Sema4D also produce alteration on the blood-brain barrier (BBB) by disrupting endothelial tight junctions and thus increasing its permeability. BBB damage has been related to higher infiltration of immune cells mediated by increasing levels of Sema4D in MS [4, 39]. As opposed to Sema3A, Sema4D is pro-angiogenic and promotes endothelial cell migration via plexin-B1-

Axon myelination in the CNS is essential for regulating fast and slow axonal transport rates. Myelination requires interaction among axons, oligodendrocytes, and semaphorins. Semaphorins regulate the migration of oligodendrocyte precursor cells (OPC) during normal development and toward demyelinated lesions. Demyelinization, caused by loss of oligodendrocytes and myelin sheaths around axons, is a pathological condition that results in axonal dysfunction, degeneration and loss of sensory and motors neurons [2, 4, 41–43]. Oligodendrocyte death can be produced by genetic defects, infections, autoimmune reactions, and trauma, along with unknown causes. In some CNS pathologies related to myelination, astrocytes clear off myelin debris, modulating oligodendrocyte activity, myelin maintenance, and its synthesis [43]. Semaphorins (Sema3A, Sema4D, Sema5A, Sema6A, and Sema7A) inhibit OPC recruitment into demyelinated lesions and its differentiation to oligodendrocytes [9, 42, 44, 45]. Sema4D, Sema6, and Sema7A have been detected in myelin, and their expression found strongly upregulated in

Sema4D, formerly known as CD100, was called the "immune semaphorin" because it was originally found in lymphocytes [3]. The Sema4D receptor in neuronal cells is plexin B1, whereas in immune cells, besides binding to plexin B1, Sema4D also binds to a signaling surface receptor CD72. CD72 is considered a regulatory receptor, because it activates suppressive signals and prevents some forms of autoimmunity [46, 47]. Sema4D is a membrane-bound protein that can be proteolytically cleaved by MT1-MMP metalloprotease, releasing a 120-kDa soluble form of Sema4D, which can act paracrinally on other systems [40, 47]. Immune semaphorins also include Sema3A, Sema4A, Sema6D, and Sema7A expressed on T-cells, B-cells, natural killer cells, neutrophils, platelets, and mature dendritic cells (DC) [39, 47]. The neuronal system sense changes to maintain CNS homeostasis and communicates to the immune system by soluble factors to inhibit further inflammatory responses. For instance, neurons control T-cell and glia functions mediated by membrane-bound or secreted molecules such as semaphorins, neurotrophins, neurotransmitters, neuropeptides, and cytokines [48, 49]. Sema3A and Sema7A expression in neurons attenuate T-cell activation, proliferation, and function through T-cell receptor signaling [49–51]. Sema3A, additionally, downregulates autoimmunity by suppressing B- and T-cell-mediated autoimmune over-activity

*Neurons - Dendrites and Axons*

**3. Semaphorin regulatory functions on neuronal and non-neuronal cells**

The roles of Sema3A and Sema4D are to produce alteration of both actin and microtubule dynamics in the cytoskeleton organization (ratio of the polymerization/ depolymerization rates). The effects of Sema3A and Sema4D on actin dynamics include the downregulation of PI3K-Akt signaling pathway, inhibiting integrinmediated adhesion as well as repulsive effects on axonal growing associated to actin-rich structure loss of lamellipodia and filopodia as part of the cofilin pathway triggered by Sema3A, or activation of myosin II (MyoII) and F-actin bundles promoted by Sema4D-ROCK signaling [2, 23, 24]. Sema3A additionally mediates an increase of the nonphosphorylated active form of myosin II (MyoII) and decreases the phosphorylation levels of Ezrin, Radixin, and Moesin (ERM) proteins. The nonphosphorylated active form of MyoII promotes retraction, while low ERM phosphorylation reduces the crosslinking between actin filaments and the plasma membrane [2, 25, 26]. Regarding microtubule dynamics, Sema4D signaling induces the inactivation of CRMP-2 by glycogen synthase kinase 3 beta (GSK3B)-mediated phosphorylation, leading to reduced binding of CRMP-2 to tubulin and consequently limiting its stabilizing function at the plus end of microtubules. Sema3A induces a similar CRMP-2-inactivating mechanism, yet requiring phosphorylation by cyclin-

**3.1 Axonal degeneration associated to cytoskeleton organization**

dependent kinase 5 (Cdk5) at Ser522 and GSK3B at Thr509/514 [2, 21, 22].

with the regeneration of damaged CNS axons [6, 11, 15, 27, 28].

function following spinal cord injury in adult zebrafish [36].

**3.3 Semaphorin function on axonal regeneration**

**3.2 Axonal degeneration associated to synaptogenesis and synaptic plasticity**

Synapsis formation of the neuronal network requires local participation of cell adhesion molecules, extracellular proteins, and axon guidance molecules at axodendritic sites [6]. Sema3A and VEGF signaling have been proposed to actively modulate the synaptogenesis and synaptic plasticity, since they are dysregulated in neurological diseases, such as AD [4, 16, 17]. Proper regulation of the synapse formation and dendritic branching contributes to a normal balance between excitatory and inhibitory synaptic transmission; dysregulation of this balance would interfere

Models of axonal regeneration have been studied after spinal cord injury, which

can produce a permanent damage because axonal growth and regeneration are limited after injury [29]. In adult mammals, some myelin proteins produced by myelinating oligodendrocytes, such as Nogo-A, MAG and OMgp, inhibit spinal cord regeneration [4]. Additionally, glial cells release chondroitin sulfate proteoglycans (CSPGs) and lecticans, such as neurocan, brevican, phosphacan, and tenascin to form the neuronal extracellular matrix (perineuronal nets). The perineuronal nets, together with other extracellular proteins, such as, ephrins, slits, netrins, bone morphogenic proteins, Wnts, and semaphorins are among the molecules most likely involved in limiting axonal regeneration [4, 30–33]. However, the function of semaphorins is dependent on the cellular context and may also favor axon regeneration. For instance, nerve growth factor (NGF) co-injected with Sema3A in trigeminal neuronal cell culture induced neuron regeneration [34]. Sema3A has also been implicated in the restoration of functionally motor innervation required to regenerate fibers [35]. Sema4D has shown enhanced locomotor recovery and axon regeneration when expressed in motoneurons, attributed to regulation of microglia

**24**

#### **3.4 Semaphorin function on revascularization**

Revascularization (restoration of perfusion) is regulated by several growth factors secreted from endothelial cells, such as VEGFA, FGF, and PDGFs [4]. Class 3 semaphorins are considered anti-angiogenic semaphorins (e.g., Sema3A, Sema3E, and Sema3F), because they interfere with the effect of VEGF by competing for the same NRP receptor [37, 38]. Sema3A not only targets the actin cytoskeleton, but also the assembly/disassembly of focal adhesions, altering migration, proliferation, and adherence of endothelial cells [37]. Sema3A and Sema4D also produce alteration on the blood-brain barrier (BBB) by disrupting endothelial tight junctions and thus increasing its permeability. BBB damage has been related to higher infiltration of immune cells mediated by increasing levels of Sema4D in MS [4, 39]. As opposed to Sema3A, Sema4D is pro-angiogenic and promotes endothelial cell migration via plexin-B1- PI3K-Akt signaling pathway [37, 40].

#### **3.5 Semaphorin function on remyelination**

Axon myelination in the CNS is essential for regulating fast and slow axonal transport rates. Myelination requires interaction among axons, oligodendrocytes, and semaphorins. Semaphorins regulate the migration of oligodendrocyte precursor cells (OPC) during normal development and toward demyelinated lesions. Demyelinization, caused by loss of oligodendrocytes and myelin sheaths around axons, is a pathological condition that results in axonal dysfunction, degeneration and loss of sensory and motors neurons [2, 4, 41–43]. Oligodendrocyte death can be produced by genetic defects, infections, autoimmune reactions, and trauma, along with unknown causes. In some CNS pathologies related to myelination, astrocytes clear off myelin debris, modulating oligodendrocyte activity, myelin maintenance, and its synthesis [43]. Semaphorins (Sema3A, Sema4D, Sema5A, Sema6A, and Sema7A) inhibit OPC recruitment into demyelinated lesions and its differentiation to oligodendrocytes [9, 42, 44, 45]. Sema4D, Sema6, and Sema7A have been detected in myelin, and their expression found strongly upregulated in oligodendrocytes located near the injury site [9, 2, 45].

#### **3.6 Semaphorin function on immune responses**

Sema4D, formerly known as CD100, was called the "immune semaphorin" because it was originally found in lymphocytes [3]. The Sema4D receptor in neuronal cells is plexin B1, whereas in immune cells, besides binding to plexin B1, Sema4D also binds to a signaling surface receptor CD72. CD72 is considered a regulatory receptor, because it activates suppressive signals and prevents some forms of autoimmunity [46, 47]. Sema4D is a membrane-bound protein that can be proteolytically cleaved by MT1-MMP metalloprotease, releasing a 120-kDa soluble form of Sema4D, which can act paracrinally on other systems [40, 47]. Immune semaphorins also include Sema3A, Sema4A, Sema6D, and Sema7A expressed on T-cells, B-cells, natural killer cells, neutrophils, platelets, and mature dendritic cells (DC) [39, 47]. The neuronal system sense changes to maintain CNS homeostasis and communicates to the immune system by soluble factors to inhibit further inflammatory responses. For instance, neurons control T-cell and glia functions mediated by membrane-bound or secreted molecules such as semaphorins, neurotrophins, neurotransmitters, neuropeptides, and cytokines [48, 49]. Sema3A and Sema7A expression in neurons attenuate T-cell activation, proliferation, and function through T-cell receptor signaling [49–51]. Sema3A, additionally, downregulates autoimmunity by suppressing B- and T-cell-mediated autoimmune over-activity

responses [52]. In addition, cell adhesion molecules expressed by neurons, such as NCAM, cadherins, and integrins are active molecules in neurogenesis and synaptic plasticity that also can ameliorate inflammation and neurotoxic effects, while strengthening neuroprotection of immune components in pathology [48].

#### **4. Semaphorins and their current association to neurological diseases**

#### **4.1 Alzheimer's disease**

Alzheimer's disease (AD) is the most invalidating, common, and widespread elderly associated neuropathology. An estimated of over 30 million people are affected worldwide, increasing its incidence with age [53]. Patients with AD suffer progressive neuron lost, mostly from the prefrontal cortex and the hippocampus. As a consequence of neuronal death, patients experience memory, cognitive, and behavioral problems, leading within an average of less than 10 years to dementia and/or death [53]. Given its prevalence and the continuing aging of the population, AD threatens to generate an epidemic healthcare crisis in the next decades and yet its cause remains unknown. Current treatments target late symptoms, improving the patient's quality of life; however, they have a minute contribution on the disease impact and its inevitable progression. Two major features are distinct from Alzheimer's brains that have intrigued researchers since Alois Alzheimer described them in 1906: presenile plaques and neurofibrillary tangles (NFT). Plaques are extracellular insoluble aggregates, mostly composed of a misfolded amyloid beta (Aβ) peptide, whereas NFT are intraneuronal aggregates of hyperphosphorylated Tau (a microtubule-associated protein). It is yet controversial whether tangles, plaques, or both are causes or consequences of AD. Semaphorins have been long suggested to play a role in AD, because they initially were found largely expressed in adult brain tissues [54] and later found to have abnormal neurohistological patterns in affected cortical and hippocampal areas of AD brains [55], especially on vulnerable neurons [56, 57].

It has been hypothesized that Sema3A may be involved in the early stages of Alzheimer's degeneration. By analyzing the histological localization of Sema3A in vulnerable hippocampal areas that are first affected by neurodegeneration, a dysregulation in Sema3A expression and release has been proposed as a possible early sign in AD brains, observed even in neurons lacking NFT and therefore possible preceding Tau hyperphosphorylation and aggregation [57]. An intracellular form of Sema3A was also found associated to NFT, along with Plexins, hyperphosphorylated CRMP-2, and microtubule-associated protein 1B (MAP-1B) [57]. The association between Sema3A and a possible downstream Tau hyperphosphorylation may come from the kinases involved in Sema3A signaling. Yoshida et al. initially found a phosphorylated form of CRMP-2 associated to NFT and significantly higher in AD brains [58]. CRMP-2 was originally discovered form its chicken homolog, CRMP-62, as a downstream effector of semaphorin (formerly known as collapsin) signaling. Injection of blocking antibodies against CRMP-62 into dorsal root ganglion inhibited the growth cone collapse induced by Sema3A, suggesting that CRMP-62 is a downstream effector in Sema3A signaling [59]. Since then, CRMP-2 has been associated to NFT in AD [58] and found phosphorylated as a result of semaphorin signaling [60, 61]. The signaling mechanism involves phosphorylation of CRMP-2 by GSK3B after a priming phosphorylation at Ser522 [61, 62]. The phosphorylation at Ser522 is required for further phosphorylation of GSK3B. In rat models, Cdk5 has been found responsible of Ser522 phosphorylation, priming the phosphorylation site of GSK3B both *in vitro* and *in vivo* [63, 64]. The sequential

**27**

*Roles of Semaphorins in Neurodegenerative Diseases DOI: http://dx.doi.org/10.5772/intechopen.82046*

tion, and microtubule destabilization observed in AD [66].

phosphorylation of CRMP-2 reduces its affinity to tubulin and triggers microtubule destabilization and Sema3A-mediated growth cone collapse associated to AD pathogenesis [63, 64]. Other kinases, such as Fyn, cyclin-dependent kinase 1, and dual specificity tyrosine-phosphorylation-regulated kinase 2 may also be involved in the priming phosphorylation at Ser522 [61, 64, 65]. The participating kinases and the Sema3A-mediated sequential phosphorylation mechanisms of CRMP-2 are strikingly similar to the pathway leading to Tau hyperphosphorylation, aggrega-

A recent study also links Tau phosphorylation to Sema3A signaling by discovering several single-nucleotide polymorphisms (SNPs) associated to AD in the PLXNA4 gene, which codifies for plexin A4 [62]. Most of the top-ranked SNPs associated to AD were located in the region coding the Sema3A-binding site [62]. Cells expressing PLXNA4 and stimulated with Sema3A showed Sema3A-induced phosphorylation of Tau, enhanced by overexpression of the full-length PLXNA4 receptor, whereas expression of soluble forms of PLXNA4 inhibited Tau phosphorylation, presumably by binding Sema3A and competing with the endogenous Plexin receptor, both in a cell line model and in rat hippocampal neurons [62]. The full-length PLXNA4 expression was found higher in AD brains, and also significantly correlates with clinical and neuropathological disease severity measures, such as dementia. The Sema3A-induced kinase activities affecting CRMP-2 and Tau may ultimately lead to neurofibrillary tangle formation and neuronal dead in AD. If Sema3A signaling is effectively involved in the early stages of neurodegeneration, it would be worth to further study its association with AD toward the discovery of new biomarkers and drugs, such as specific kinase inhibitors (some of them already in clinical trial) [67]. An example of a different treatment approach involves modulating the interaction of semaphorins with the neuronal extracellular matrix or perineuronal nets. Differential expression of several proteins related to the extracellular matrix, among them Sema3C, has been found in AD-vulnerable brain areas [56]. Additionally, memory restoration in AD mice models has been achieved by digesting CSPs, a major component of perineuronal nets, using chondroitinase [68, 69]. Disruption of perineuronal nets presumably allows the formation of new synapsis sites and thus increases adult brain plasticity. An important effector of perineuronal nets is Sema3A by binding to chondroitin sulfate, a main component of CSPs [70]. A recent study showed restoration of object recognition memory in a tauopathy mice model via reducing Sema3A binding to perineuronal nets by perirhinal cortex injections of an inhibitory proteoglycan-neutralizing antibody against chondroitin 4-sulfate [69]. Therefore, blocking the binding of Sema3A to perineuronal nets can restore memory function in adult AD-mice model. It is also interesting to note the bifunctional effect of semaphorins in AD. For instance, Sema3A has been shown to promote apoptosis and neurodegeneration [57, 61], whereas Sema3C has been related to neuroprotection [56, 71]. Such duality, along with several other genetic, environmental, and aging components, gives to AD its multifactorial category. Genetic factors are thought to account for over 50% of the disease, yet these risk factors are not determinants to causing AD. In rare cases of early-onset familial AD, the disease is linked to mutations on genes involving Aβ metabolism, such as the amyloid precursor protein (APP) and presenilin (PSEN1/2) genes. APP is a transmembrane protein from which Aβ peptide is generated by the cleavage of a gamma secretase complex. Presenilin-1 and presenilin-2 are part of the gamma secretase complex. However, in the most common sporadic (nonfamilial) late-onset AD, the genetic variants only explain part of the disease etiology. Several genes have been considered a risk factor, such as the APOE-ε4 polymorphic isoform of the apolipoprotein E gene (APOE), the main cholesterol carrier in the CNS. The role of apolipoprotein E in AD is, however, poorly understood and thought to be related to Aβ degradation [72]. Semaphorin polymorphs

#### *Roles of Semaphorins in Neurodegenerative Diseases DOI: http://dx.doi.org/10.5772/intechopen.82046*

*Neurons - Dendrites and Axons*

**4.1 Alzheimer's disease**

able neurons [56, 57].

responses [52]. In addition, cell adhesion molecules expressed by neurons, such as NCAM, cadherins, and integrins are active molecules in neurogenesis and synaptic plasticity that also can ameliorate inflammation and neurotoxic effects, while strengthening neuroprotection of immune components in pathology [48].

**4. Semaphorins and their current association to neurological diseases**

Alzheimer's disease (AD) is the most invalidating, common, and widespread elderly associated neuropathology. An estimated of over 30 million people are affected worldwide, increasing its incidence with age [53]. Patients with AD suffer progressive neuron lost, mostly from the prefrontal cortex and the hippocampus. As a consequence of neuronal death, patients experience memory, cognitive, and behavioral problems, leading within an average of less than 10 years to dementia and/or death [53]. Given its prevalence and the continuing aging of the population, AD threatens to generate an epidemic healthcare crisis in the next decades and yet its cause remains unknown. Current treatments target late symptoms, improving the patient's quality of life; however, they have a minute contribution on the disease impact and its inevitable progression. Two major features are distinct from Alzheimer's brains that have intrigued researchers since Alois Alzheimer described them in 1906: presenile plaques and neurofibrillary tangles (NFT). Plaques are extracellular insoluble aggregates, mostly composed of a misfolded amyloid beta (Aβ) peptide, whereas NFT are intraneuronal aggregates of hyperphosphorylated Tau (a microtubule-associated protein). It is yet controversial whether tangles, plaques, or both are causes or consequences of AD. Semaphorins have been long suggested to play a role in AD, because they initially were found largely expressed in adult brain tissues [54] and later found to have abnormal neurohistological patterns in affected cortical and hippocampal areas of AD brains [55], especially on vulner-

It has been hypothesized that Sema3A may be involved in the early stages of Alzheimer's degeneration. By analyzing the histological localization of Sema3A in vulnerable hippocampal areas that are first affected by neurodegeneration, a dysregulation in Sema3A expression and release has been proposed as a possible early sign in AD brains, observed even in neurons lacking NFT and therefore possible preceding Tau hyperphosphorylation and aggregation [57]. An intracellular form of Sema3A was also found associated to NFT, along with Plexins, hyperphosphorylated CRMP-2, and microtubule-associated protein 1B (MAP-1B) [57]. The association between Sema3A and a possible downstream Tau hyperphosphorylation may come from the kinases involved in Sema3A signaling. Yoshida et al. initially found a phosphorylated form of CRMP-2 associated to NFT and significantly higher in AD brains [58]. CRMP-2 was originally discovered form its chicken homolog, CRMP-62, as a downstream effector of semaphorin (formerly known as collapsin) signaling. Injection of blocking antibodies against CRMP-62 into dorsal root ganglion inhibited the growth cone collapse induced by Sema3A, suggesting that CRMP-62 is a downstream effector in Sema3A signaling [59]. Since then, CRMP-2 has been associated to NFT in AD [58] and found phosphorylated as a result of semaphorin signaling [60, 61]. The signaling mechanism involves phosphorylation of CRMP-2 by GSK3B after a priming phosphorylation at Ser522 [61, 62]. The phosphorylation at Ser522 is required for further phosphorylation of GSK3B. In rat models, Cdk5 has been found responsible of Ser522 phosphorylation, priming the phosphorylation site of GSK3B both *in vitro* and *in vivo* [63, 64]. The sequential

**26**

phosphorylation of CRMP-2 reduces its affinity to tubulin and triggers microtubule destabilization and Sema3A-mediated growth cone collapse associated to AD pathogenesis [63, 64]. Other kinases, such as Fyn, cyclin-dependent kinase 1, and dual specificity tyrosine-phosphorylation-regulated kinase 2 may also be involved in the priming phosphorylation at Ser522 [61, 64, 65]. The participating kinases and the Sema3A-mediated sequential phosphorylation mechanisms of CRMP-2 are strikingly similar to the pathway leading to Tau hyperphosphorylation, aggregation, and microtubule destabilization observed in AD [66].

A recent study also links Tau phosphorylation to Sema3A signaling by discovering several single-nucleotide polymorphisms (SNPs) associated to AD in the PLXNA4 gene, which codifies for plexin A4 [62]. Most of the top-ranked SNPs associated to AD were located in the region coding the Sema3A-binding site [62]. Cells expressing PLXNA4 and stimulated with Sema3A showed Sema3A-induced phosphorylation of Tau, enhanced by overexpression of the full-length PLXNA4 receptor, whereas expression of soluble forms of PLXNA4 inhibited Tau phosphorylation, presumably by binding Sema3A and competing with the endogenous Plexin receptor, both in a cell line model and in rat hippocampal neurons [62]. The full-length PLXNA4 expression was found higher in AD brains, and also significantly correlates with clinical and neuropathological disease severity measures, such as dementia. The Sema3A-induced kinase activities affecting CRMP-2 and Tau may ultimately lead to neurofibrillary tangle formation and neuronal dead in AD. If Sema3A signaling is effectively involved in the early stages of neurodegeneration, it would be worth to further study its association with AD toward the discovery of new biomarkers and drugs, such as specific kinase inhibitors (some of them already in clinical trial) [67]. An example of a different treatment approach involves modulating the interaction of semaphorins with the neuronal extracellular matrix or perineuronal nets. Differential expression of several proteins related to the extracellular matrix, among them Sema3C, has been found in AD-vulnerable brain areas [56]. Additionally, memory restoration in AD mice models has been achieved by digesting CSPs, a major component of perineuronal nets, using chondroitinase [68, 69]. Disruption of perineuronal nets presumably allows the formation of new synapsis sites and thus increases adult brain plasticity. An important effector of perineuronal nets is Sema3A by binding to chondroitin sulfate, a main component of CSPs [70]. A recent study showed restoration of object recognition memory in a tauopathy mice model via reducing Sema3A binding to perineuronal nets by perirhinal cortex injections of an inhibitory proteoglycan-neutralizing antibody against chondroitin 4-sulfate [69]. Therefore, blocking the binding of Sema3A to perineuronal nets can restore memory function in adult AD-mice model.

It is also interesting to note the bifunctional effect of semaphorins in AD. For instance, Sema3A has been shown to promote apoptosis and neurodegeneration [57, 61], whereas Sema3C has been related to neuroprotection [56, 71]. Such duality, along with several other genetic, environmental, and aging components, gives to AD its multifactorial category. Genetic factors are thought to account for over 50% of the disease, yet these risk factors are not determinants to causing AD. In rare cases of early-onset familial AD, the disease is linked to mutations on genes involving Aβ metabolism, such as the amyloid precursor protein (APP) and presenilin (PSEN1/2) genes. APP is a transmembrane protein from which Aβ peptide is generated by the cleavage of a gamma secretase complex. Presenilin-1 and presenilin-2 are part of the gamma secretase complex. However, in the most common sporadic (nonfamilial) late-onset AD, the genetic variants only explain part of the disease etiology. Several genes have been considered a risk factor, such as the APOE-ε4 polymorphic isoform of the apolipoprotein E gene (APOE), the main cholesterol carrier in the CNS. The role of apolipoprotein E in AD is, however, poorly understood and thought to be related to Aβ degradation [72]. Semaphorin polymorphs

have also been studied given their relevance in neuronal apoptosis and the findings of semaphorin polymorphisms related to other syndromes. The first attempts in relating semaphorin SNPs with AD were, however, unfruitful. Evaluation of two exonic SNPs of semaphorin 3A and 4D genes in patients with AD showed no correlation, even though modeling analysis predicted a damaged variant of the affected proteins [73]. Recently, however, a novel proposed method for detecting hidden SNPs that would otherwise appear undetected by commonly used tests found six SNPs on noncoding regions near the semaphorin 5A gene [74]. Schott et al. [75] also found in a noncodifying region of the SEMA3C gene a polymorphism associated to posterior cortical atrophy, a variant of AD. The SEMA3C SNP, therefore, suggests a role of Sema3C during development that may influence later neurodegeneration associated to specific brain regions that ultimately lead to differential degeneration phenotypes [75]. In light of these recent associations of semaphorins to AD [62, 74, 75], semaphorin gene variants and their receptors are expected to participate as a risk factor of AD and its associated neuropathologies, opening a relatively underexplored door toward new discoveries.

#### **4.2 Parkinson's disease**

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder after AD, affecting up to 1% of the worldwide population above 60 years old [76]. PD patients suffer a progressive and selective loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc), which innervates neurons in the dorsal striatum and regulates its effects on motor functions. The result of neurodegeneration manifests mostly with movement disorders or dyskinesia, where tremor at rest, rigidity, and bradykinesia are cardinal for diagnosis [76]. The reason why SNpc dopaminergic neurons die is not well understood. A composite interaction between genetics and environmental factors in the context of aging has been intensively studied to find the causes, preventing strategies and potential therapies of PD. Semaphorins in their role of apoptotic mediators in neurodegeneration have early on been suggested to be involved in the pathogenesis of PD [77–80].

Even though it is currently accepted that genetic plays a minor role in sporadic (nonfamilial) PD based on studies with relatives [81], several genes are known to be involved in the disease etiology and progression. For instance, mutations in the SNCA gene are known to be associated with familial PD and increased risk of sporadic PD. The SNCA gene encodes alpha-synuclein, which is the main protein found in Lewy bodies as insoluble aggregates inside SNpc neurons of patients with PD. Interestingly, population genetic studies have also found SNPs in the Sema5A gene that may be related to PD. In the pioneer work of Maraganore et al., 11 SNPs were associated to PD in Caucasian Americans by using a two-stage whole-genome association analysis including 198,345 SNPs. The SNP with the lowest p-value associated to increased risk of PD was located in the Sema5A gene (rs7702187 polymorphism, corresponding to a thymine substituted by adenine in an intronic sequence) [82]. Given the relevance of semaphorins in neuronal apoptosis, the polymorphism in Sema5A found by Maraganore et al. [82] was soon assessed by different research groups, though having conflicting results that still remain unclear. The controversies may come from the different populations evaluated in each analysis. Some studies have shown that the rs7702187 polymorphism is not associated to PD [83, 84] or even conflict to the extent of finding the polymorphic variant protective rather than a risk factor on a population-dependent basis [85]. Taiwanese Asians showed significant associations of the Sema5A rs7702187 polymorphism [85], whereas Finnish Caucasians, Polish Caucasians, Singapore Asians, and Chinese Han populations were not associated to PD [83–86]. In addition, a different SNP, the rs3798097

**29**

treatment.

*Roles of Semaphorins in Neurodegenerative Diseases DOI: http://dx.doi.org/10.5772/intechopen.82046*

(C > T), located in the 5'UTR of the Sema5A gene, was also found associated with PD [85]. Ding et al. [86] showed that although the genotypes are not necessarily associated to PD in a Chinese Han population, the haplotypes involving these two SNPs in the context of a particular ethnicity may be implicated in the disease by finding the AC haplotype associated with an increased risk of PD compared to the common TC haplotype, whereas the AT haplotype was found protective against PD [86]. A more recent meta-analysis on the rs7702187 polymorphism concluded that the A allele frequency was associated to increased risk of PD only in Western population [87]. Both polymorphisms do not affect the sequence of the protein, but rather may be regulatory sequences affecting expression dynamics of Sema5A. These SNPs may be associated to PD; however, less studied polymorphic variants together with other cellular and molecular factors should be considered as well, such as the expression of other semaphorin classes and their receptors that may result as a confounding factor across different population genetic studies. Besides the genetic highlights on PD, the mechanisms by which semaphorins participate in the disease etiology and progression are poorly understood. Although semaphorins had been suggested to promote neurodegeneration in PD, limited studies were known to link semaphorins in the context of the disease pathogenesis [77, 78, 88, 89]. After a decade of research since the study of Maraganore et al. [82], several lines of evidence indicate possible direct mechanisms of semaphorins (though, not Sema5A) in PD etiology. Recent evidence in a neurotoxin (MPTP) induced PD mouse model directly involves Sema3A effects through Rho-ROCK signaling pathway. Rho kinase inhibition as well as heterozygous mice knockouts in both Rho and ROCK protect from MPTP-induced damage of dopaminergic neurons, increase dopamine and its metabolic products at the striatum, showed reduced protein expression of Sema3A and its receptors, plexin A and NRP-1, and overall alleviate the behavior damage compared to control PD mice [90–93]. The effects of Sema3A on Rho-ROCK signaling pathway could mediate several cytoskeleton effectors, contributing to growth cone collapse as well as regulation of neuronal apoptosis. Animal models and SNpc of human brains from PD-affected subjects show apparent neuronal apoptotic processes, probably triggered by oxidative stress [94]. Whether semaphorins are directly involved in causing neuronal apoptosis in PD is debatable and may be associated in part to their specific receptors and signaling pathways. For instance, although Sema3A through plexin A/ NRP-1 and activation of Rho kinase was found to promote dopaminergic damage [92], Sema7A has been found protective against ROS-mediated neurodegeneration [95]. Sema7A binds to integrin receptors and could potentially regulate apoptosis through different mechanism. Sema7A reduces the large axonal arborization on dopaminergic neurons, which potentially decreases mitochondrial oxygen demand, ROS production, and neuronal vulnerability observed in PD [95]. However, even different ligands to the same receptor for Sema3A have been found protective against neuronal apoptosis. For instance, VEGF shows neuroprotection in PD models likely by binding to neuropilin receptors, though it is unclear whether the downstream VEGF signaling effectors differ from the semaphorin transduction pathway or VEGF indirectly promotes protection by competition to the same receptor. Alternatively, VEGF could mediate apoptosis by other processes such angiogenesis [89]. It would be interesting to evaluate in future research different ROS-mediated apoptotic pathways and their interplay with semaphorininduced signaling, such as the phosphorylation targets of ROCK resulting in growth cone collapse (which could mediate CRMP-2 phosphorylation by a similar mechanism to what described previously for AD), to find out how these pathways are regulated in an effort to evaluate new drug candidates for PD prevention and

#### *Roles of Semaphorins in Neurodegenerative Diseases DOI: http://dx.doi.org/10.5772/intechopen.82046*

*Neurons - Dendrites and Axons*

plored door toward new discoveries.

**4.2 Parkinson's disease**

have also been studied given their relevance in neuronal apoptosis and the findings of semaphorin polymorphisms related to other syndromes. The first attempts in relating semaphorin SNPs with AD were, however, unfruitful. Evaluation of two exonic SNPs of semaphorin 3A and 4D genes in patients with AD showed no correlation, even though modeling analysis predicted a damaged variant of the affected proteins [73]. Recently, however, a novel proposed method for detecting hidden SNPs that would otherwise appear undetected by commonly used tests found six SNPs on noncoding regions near the semaphorin 5A gene [74]. Schott et al. [75] also found in a noncodifying region of the SEMA3C gene a polymorphism associated to posterior cortical atrophy, a variant of AD. The SEMA3C SNP, therefore, suggests a role of Sema3C during development that may influence later neurodegeneration associated to specific brain regions that ultimately lead to differential degeneration phenotypes [75]. In light of these recent associations of semaphorins to AD [62, 74, 75], semaphorin gene variants and their receptors are expected to participate as a risk factor of AD and its associated neuropathologies, opening a relatively underex-

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder after AD, affecting up to 1% of the worldwide population above 60 years old [76]. PD patients suffer a progressive and selective loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc), which innervates neurons in the dorsal striatum and regulates its effects on motor functions. The result of neurodegeneration manifests mostly with movement disorders or dyskinesia, where tremor at rest, rigidity, and bradykinesia are cardinal for diagnosis [76]. The reason why SNpc dopaminergic neurons die is not well understood. A composite interaction between genetics and environmental factors in the context of aging has been intensively studied to find the causes, preventing strategies and potential therapies of PD. Semaphorins in their role of apoptotic mediators in neurodegeneration have

early on been suggested to be involved in the pathogenesis of PD [77–80].

Even though it is currently accepted that genetic plays a minor role in sporadic (nonfamilial) PD based on studies with relatives [81], several genes are known to be involved in the disease etiology and progression. For instance, mutations in the SNCA gene are known to be associated with familial PD and increased risk of sporadic PD. The SNCA gene encodes alpha-synuclein, which is the main protein found in Lewy bodies as insoluble aggregates inside SNpc neurons of patients with PD. Interestingly, population genetic studies have also found SNPs in the Sema5A gene that may be related to PD. In the pioneer work of Maraganore et al., 11 SNPs were associated to PD in Caucasian Americans by using a two-stage whole-genome association analysis including 198,345 SNPs. The SNP with the lowest p-value associated to increased risk of PD was located in the Sema5A gene (rs7702187 polymorphism, corresponding to a thymine substituted by adenine in an intronic sequence) [82]. Given the relevance of semaphorins in neuronal apoptosis, the polymorphism in Sema5A found by Maraganore et al. [82] was soon assessed by different research groups, though having conflicting results that still remain unclear. The controversies may come from the different populations evaluated in each analysis. Some studies have shown that the rs7702187 polymorphism is not associated to PD [83, 84] or even conflict to the extent of finding the polymorphic variant protective rather than a risk factor on a population-dependent basis [85]. Taiwanese Asians showed significant associations of the Sema5A rs7702187 polymorphism [85], whereas Finnish Caucasians, Polish Caucasians, Singapore Asians, and Chinese Han populations were not associated to PD [83–86]. In addition, a different SNP, the rs3798097

**28**

(C > T), located in the 5'UTR of the Sema5A gene, was also found associated with PD [85]. Ding et al. [86] showed that although the genotypes are not necessarily associated to PD in a Chinese Han population, the haplotypes involving these two SNPs in the context of a particular ethnicity may be implicated in the disease by finding the AC haplotype associated with an increased risk of PD compared to the common TC haplotype, whereas the AT haplotype was found protective against PD [86]. A more recent meta-analysis on the rs7702187 polymorphism concluded that the A allele frequency was associated to increased risk of PD only in Western population [87]. Both polymorphisms do not affect the sequence of the protein, but rather may be regulatory sequences affecting expression dynamics of Sema5A. These SNPs may be associated to PD; however, less studied polymorphic variants together with other cellular and molecular factors should be considered as well, such as the expression of other semaphorin classes and their receptors that may result as a confounding factor across different population genetic studies.

Besides the genetic highlights on PD, the mechanisms by which semaphorins participate in the disease etiology and progression are poorly understood. Although semaphorins had been suggested to promote neurodegeneration in PD, limited studies were known to link semaphorins in the context of the disease pathogenesis [77, 78, 88, 89]. After a decade of research since the study of Maraganore et al. [82], several lines of evidence indicate possible direct mechanisms of semaphorins (though, not Sema5A) in PD etiology. Recent evidence in a neurotoxin (MPTP) induced PD mouse model directly involves Sema3A effects through Rho-ROCK signaling pathway. Rho kinase inhibition as well as heterozygous mice knockouts in both Rho and ROCK protect from MPTP-induced damage of dopaminergic neurons, increase dopamine and its metabolic products at the striatum, showed reduced protein expression of Sema3A and its receptors, plexin A and NRP-1, and overall alleviate the behavior damage compared to control PD mice [90–93]. The effects of Sema3A on Rho-ROCK signaling pathway could mediate several cytoskeleton effectors, contributing to growth cone collapse as well as regulation of neuronal apoptosis. Animal models and SNpc of human brains from PD-affected subjects show apparent neuronal apoptotic processes, probably triggered by oxidative stress [94]. Whether semaphorins are directly involved in causing neuronal apoptosis in PD is debatable and may be associated in part to their specific receptors and signaling pathways. For instance, although Sema3A through plexin A/ NRP-1 and activation of Rho kinase was found to promote dopaminergic damage [92], Sema7A has been found protective against ROS-mediated neurodegeneration [95]. Sema7A binds to integrin receptors and could potentially regulate apoptosis through different mechanism. Sema7A reduces the large axonal arborization on dopaminergic neurons, which potentially decreases mitochondrial oxygen demand, ROS production, and neuronal vulnerability observed in PD [95]. However, even different ligands to the same receptor for Sema3A have been found protective against neuronal apoptosis. For instance, VEGF shows neuroprotection in PD models likely by binding to neuropilin receptors, though it is unclear whether the downstream VEGF signaling effectors differ from the semaphorin transduction pathway or VEGF indirectly promotes protection by competition to the same receptor. Alternatively, VEGF could mediate apoptosis by other processes such angiogenesis [89]. It would be interesting to evaluate in future research different ROS-mediated apoptotic pathways and their interplay with semaphorininduced signaling, such as the phosphorylation targets of ROCK resulting in growth cone collapse (which could mediate CRMP-2 phosphorylation by a similar mechanism to what described previously for AD), to find out how these pathways are regulated in an effort to evaluate new drug candidates for PD prevention and treatment.

Paradoxically, the Sema3A found to promote neurodegeneration in PD pathogenesis, at the same time may be useful for steam cell transplantation therapy in PD patients [96–99]. Given that semaphorins participate in the formation of the nigrostriatal pathway during prenatal development, they have also been proposed to guide axons to their appropriate targets after possible cell replacement therapy with dopaminergic neurons [96, 100–105]. Embryonic stem cells differentiated to tyrosine hydroxylase-expressing neurons have been shown to have similar phenotype, expression of neuropilins, and response to Class 3 semaphorins than embryonic ventral mesencephalon neurons [96, 97, 106]. Via neuropilin-mediated signaling, Sema3A increases axonal length in collagen gel coculture experiments. Sema3C, besides increasing length, also attracts axons, whereas Sema3F produces either no effect or axon repulsion [96, 97]. Semaphorin axonal guidance results are promising toward the recovery of parkinsonian symptoms in transplanted PD animal models [98, 99]. Therefore, even though semaphorins may be directly involved in promoting PD neurodegeneration, they could also be a strategy to restore the dopaminergic function by providing axon guidance cues after embryonic stem cell intranigral transplantation.

#### **4.3 Charcot-Marie-Tooth disease**

Charcot-Marie-Tooth disease (CMT) is an inherited peripheral neuropathy associated with mutations in more than 90 different genes. CMT is divided into different forms based on the inheritance pattern and neurophysiological observations. The most common types are autosomal-dominant forms, and they are categorized into demyelinating with reduced nerve conduction velocities (CMT type 1) and axonal-loss type with relatively normal nerve conduction velocities (CMT type 2). Patients with CMT type 2 comprise about 20% of all cases [107–110].

Mutations in the gene *GARS*, encoding glycyl-tRNA synthetase (GlyRS), have been related to peripheral nerve degeneration and CMT type 2 [111]. In addition, mutated GlyRS has shown to bind neuropilin-1 in mice [112]. Besides its housekeeping intracellular function during protein synthesis, GlyRS can be secreted and produce different cellular effects from the extracellular space [113]. In *Drosophila*, the Cader lab showed that mutant GlyRS is secreted by muscles and interacts with the neuromuscular junction [114]. Recently, they showed that the P234KY mutant version of GlyRS (mutation associated to CMT type 2) colocalizes with plexin B in presynaptic neurons. Also, Sema2A overexpression, but not Sema1A overexpression, decreased the effect that mutant GlyRS produced on muscle contraction, suggesting that plexin B signaling could be affected by mutated GlyRS by competition with Sema2A [115]. Also, other ligands for neuropilin should be taken into account, such as VEGF. He et al. suggest that CMT type 2 mutations in GlyRS promote its abnormal binding to neuropilin-1, antagonizing the binding of VEGF and blocking the VEGF/neuropilin-1 signaling essential for survival and function of motor neurons [112]. Nevertheless, the neuropilin sequestration by mutant GlyRS has shown to be less detrimental in other tissues, given that this abnormal interaction is permissive to maturation and maintenance of the vasculature in CMT type 2 mice [116].

It is important to consider that in addition to the extracellular function, mutated GlyRS can have abnormal intracellular functions that could also contribute to the CMT pathogenesis, suggesting that multiple mechanisms could be participating. For example, human GlyRS mutations related to CMT (S581 L and G598A E71G, L129P, S211F, G240R, E279D, H418R, and G526R) have shown to have a gain-offunction effect binding to histone deacetylase 6 (HDAC6) and enhance its function, promoting α-tubulin de-acetylation and leading to axonal transport deficit. It is

**31**

(SOD1G37R mutation) [123].

*Roles of Semaphorins in Neurodegenerative Diseases DOI: http://dx.doi.org/10.5772/intechopen.82046*

tion pathways controlled by these receptors.

in ventral roots at late stages of the disease [121] [121].

In parallel, Miyazaki et al. focused on extracellular protein changes in SOD1G93A mice during the development of ALS to characterize changes in the cellular environment that could affect regeneration [122]. They found decreased Sema3A levels in the anterior half of the lumbar cord of ALS mice. Sema3A immunochemistry at ages 15 and 18 weeks showed a progressive decrease of staining in the neuropil of ALS mice compared to wild type, while Sema3A-positive astrocyte appeared [122]. In addition, it was found that *Sema3D* gene expression levels are decreased 2.5-fold with respect to wild type in another ALS mouse model

Another piece of evidence for the role of semaphorins on ALS is related to microribonucleic acids (miRNAs). miRNAs are small single-stranded, noncoding RNAs that alter gene expression through post-transcriptional regulation by

**4.4 Amyotrophic lateral sclerosis**

relevant to highlight that G598A patients have more severe distal weakness and wasting in the lower limbs, and in that same article, this mutation showed one of the strongest affinities for HDAC6 [117]. Thus, the most severe mutations in GlyRS could eventually promote abnormal interaction with both NRP1 and HDAC6. A combination of intracellular and extracellular effects could eventually explain the severity and early-onset clinical symptoms of the patients carrying the G598A mutation, as the authors suggested. Future experiments will have to address in more detail the contributions that different plexin/neuropilin ligands may have in CMT, and also link the phenotypes with abnormal activation or deactivation of transduc-

ALS is a neurological disorder with motor neuron degeneration. Neuron loss leads to paralysis in muscles and death mostly by respiratory failure. Most of the studies in animal models related to ALS use superoxide dismutase (SOD) mutations in mice (in particular, the SOD1G93A transgenic mouse), although the mechanism by which SOD mutations cause ALS is not clear. In these mice models, modifications in axons and nerve terminals are observed even before the clinical symptoms [118]. The first report linking semaphorins and ALS was published in 2006 by De Winter et al. showing increased Sema3A mRNA levels in the SOD1G93A transgenic mice model [119]. Nevertheless, a more recent report from the same lab showed that ALS mice expressing a mutant version of Sema3A (K108 N mutation that produces diminished signaling capacity) had no difference in ALS-induced decline in motor behavior, contrary to what was initially expected [120]. These last results point to a minor contribution of Sema3A to ALS pathology, although other articles are in clear contradiction with this claim. A clear example is the article published by Venkova et al. who hypothesized that Sema3A is able to trigger distal axonopathy and muscle denervation in the SOD1G93A mouse model of ALS [121]. They propose that Sema3A released from terminal Schwann cells activates plexin-A/neuropilin-1, promoting the regulation of kinases such as CDK5 and GSK3B that could alter CRMP-2 phosphorylation and leading to microtubule instability and actin cytoskeletal rearrangements. The Sema3A-mediated signaling could inhibit compensatory axon sprouting and coordination of neuromuscular junction remodeling after injury, contributing to distal axonopathy [121]. Anti-neuropilin-1 antibodies that block the Sema3A docking site in differentiated motor neuron-like cells (NSC-34) prevented Sema3A-induced growth cone collapse. Furthermore, injections of blocking antibodies delayed and even temporarily reversed the motor functional decline while prolonging the life span of SOD1G93A mice. Histologically, the antibody reduced neuromuscular junction denervation and attenuated pathologic alterations

#### *Roles of Semaphorins in Neurodegenerative Diseases DOI: http://dx.doi.org/10.5772/intechopen.82046*

*Neurons - Dendrites and Axons*

intranigral transplantation.

**4.3 Charcot-Marie-Tooth disease**

Paradoxically, the Sema3A found to promote neurodegeneration in PD pathogenesis, at the same time may be useful for steam cell transplantation therapy in PD patients [96–99]. Given that semaphorins participate in the formation of the nigrostriatal pathway during prenatal development, they have also been proposed to guide axons to their appropriate targets after possible cell replacement therapy with dopaminergic neurons [96, 100–105]. Embryonic stem cells differentiated to tyrosine hydroxylase-expressing neurons have been shown to have similar phenotype, expression of neuropilins, and response to Class 3 semaphorins than embryonic ventral mesencephalon neurons [96, 97, 106]. Via neuropilin-mediated signaling, Sema3A increases axonal length in collagen gel coculture experiments. Sema3C, besides increasing length, also attracts axons, whereas Sema3F produces either no effect or axon repulsion [96, 97]. Semaphorin axonal guidance results are promising toward the recovery of parkinsonian symptoms in transplanted PD animal models [98, 99]. Therefore, even though semaphorins may be directly involved in promoting PD neurodegeneration, they could also be a strategy to restore the dopaminergic function by providing axon guidance cues after embryonic stem cell

Charcot-Marie-Tooth disease (CMT) is an inherited peripheral neuropathy associated with mutations in more than 90 different genes. CMT is divided into different forms based on the inheritance pattern and neurophysiological observations. The most common types are autosomal-dominant forms, and they are categorized into demyelinating with reduced nerve conduction velocities (CMT type 1) and axonal-loss type with relatively normal nerve conduction velocities (CMT type 2).

Mutations in the gene *GARS*, encoding glycyl-tRNA synthetase (GlyRS), have been related to peripheral nerve degeneration and CMT type 2 [111]. In addition, mutated GlyRS has shown to bind neuropilin-1 in mice [112]. Besides its housekeeping intracellular function during protein synthesis, GlyRS can be secreted and produce different cellular effects from the extracellular space [113]. In *Drosophila*, the Cader lab showed that mutant GlyRS is secreted by muscles and interacts with the neuromuscular junction [114]. Recently, they showed that the P234KY mutant version of GlyRS (mutation associated to CMT type 2) colocalizes with plexin B in presynaptic neurons. Also, Sema2A overexpression, but not Sema1A overexpression, decreased the effect that mutant GlyRS produced on muscle contraction, suggesting that plexin B signaling could be affected by mutated GlyRS by competition with Sema2A [115]. Also, other ligands for neuropilin should be taken into account, such as VEGF. He et al. suggest that CMT type 2 mutations in GlyRS promote its abnormal binding to neuropilin-1, antagonizing the binding of VEGF and blocking the VEGF/neuropilin-1 signaling essential for survival and function of motor neurons [112]. Nevertheless, the neuropilin sequestration by mutant GlyRS has shown to be less detrimental in other tissues, given that this abnormal interaction is permissive to maturation and maintenance of the vasculature in

It is important to consider that in addition to the extracellular function, mutated GlyRS can have abnormal intracellular functions that could also contribute to the CMT pathogenesis, suggesting that multiple mechanisms could be participating. For example, human GlyRS mutations related to CMT (S581 L and G598A E71G, L129P, S211F, G240R, E279D, H418R, and G526R) have shown to have a gain-offunction effect binding to histone deacetylase 6 (HDAC6) and enhance its function, promoting α-tubulin de-acetylation and leading to axonal transport deficit. It is

Patients with CMT type 2 comprise about 20% of all cases [107–110].

**30**

CMT type 2 mice [116].

relevant to highlight that G598A patients have more severe distal weakness and wasting in the lower limbs, and in that same article, this mutation showed one of the strongest affinities for HDAC6 [117]. Thus, the most severe mutations in GlyRS could eventually promote abnormal interaction with both NRP1 and HDAC6. A combination of intracellular and extracellular effects could eventually explain the severity and early-onset clinical symptoms of the patients carrying the G598A mutation, as the authors suggested. Future experiments will have to address in more detail the contributions that different plexin/neuropilin ligands may have in CMT, and also link the phenotypes with abnormal activation or deactivation of transduction pathways controlled by these receptors.

#### **4.4 Amyotrophic lateral sclerosis**

ALS is a neurological disorder with motor neuron degeneration. Neuron loss leads to paralysis in muscles and death mostly by respiratory failure. Most of the studies in animal models related to ALS use superoxide dismutase (SOD) mutations in mice (in particular, the SOD1G93A transgenic mouse), although the mechanism by which SOD mutations cause ALS is not clear. In these mice models, modifications in axons and nerve terminals are observed even before the clinical symptoms [118].

The first report linking semaphorins and ALS was published in 2006 by De Winter et al. showing increased Sema3A mRNA levels in the SOD1G93A transgenic mice model [119]. Nevertheless, a more recent report from the same lab showed that ALS mice expressing a mutant version of Sema3A (K108 N mutation that produces diminished signaling capacity) had no difference in ALS-induced decline in motor behavior, contrary to what was initially expected [120]. These last results point to a minor contribution of Sema3A to ALS pathology, although other articles are in clear contradiction with this claim. A clear example is the article published by Venkova et al. who hypothesized that Sema3A is able to trigger distal axonopathy and muscle denervation in the SOD1G93A mouse model of ALS [121]. They propose that Sema3A released from terminal Schwann cells activates plexin-A/neuropilin-1, promoting the regulation of kinases such as CDK5 and GSK3B that could alter CRMP-2 phosphorylation and leading to microtubule instability and actin cytoskeletal rearrangements. The Sema3A-mediated signaling could inhibit compensatory axon sprouting and coordination of neuromuscular junction remodeling after injury, contributing to distal axonopathy [121]. Anti-neuropilin-1 antibodies that block the Sema3A docking site in differentiated motor neuron-like cells (NSC-34) prevented Sema3A-induced growth cone collapse. Furthermore, injections of blocking antibodies delayed and even temporarily reversed the motor functional decline while prolonging the life span of SOD1G93A mice. Histologically, the antibody reduced neuromuscular junction denervation and attenuated pathologic alterations in ventral roots at late stages of the disease [121] [121].

In parallel, Miyazaki et al. focused on extracellular protein changes in SOD1G93A mice during the development of ALS to characterize changes in the cellular environment that could affect regeneration [122]. They found decreased Sema3A levels in the anterior half of the lumbar cord of ALS mice. Sema3A immunochemistry at ages 15 and 18 weeks showed a progressive decrease of staining in the neuropil of ALS mice compared to wild type, while Sema3A-positive astrocyte appeared [122]. In addition, it was found that *Sema3D* gene expression levels are decreased 2.5-fold with respect to wild type in another ALS mouse model (SOD1G37R mutation) [123].

Another piece of evidence for the role of semaphorins on ALS is related to microribonucleic acids (miRNAs). miRNAs are small single-stranded, noncoding RNAs that alter gene expression through post-transcriptional regulation by binding to the 3′-untranslated region of target mRNAs [124]. The Perlson lab [125] analyzed miRNA profiles from axons and somas of two ALS mouse models, SOD1 with G93A mutation and TDP43 with A315T mutation. They showed that different miRNAs were significantly altered in the axons expressing ALS mutations, but not in the somas, indicating that miRNA could be regulating local functions in motor neuron axons [125]. Later, the same lab using qRT-PCR showed that one of these miRNAs, miR126-5p, downregulates Sema3A, Sema3B, neuropilin-1, and neuropilin-2 transcript levels in HeLa cells. Primary myoblasts with the SOD1G93A mutation were transfected with miR126-5p and cultured in a distal compartment of a microfluidic chamber together with a motor neuron explant placed in the proximal compartment. They showed that in the microfluidic chamber, the rate of axons that traversed the distal compartment was increased respect to the control condition of myoblasts transfected with an irrelevant miRNA. In addition, the injection of miR126-5p to ALS mice increased the amount of intact neuromuscular junctions revealing higher innervation in treated muscles compared to the mock condition. Three parameters: Mean Stand Index (measurement of the speed at which the paws detach from the walking surface), single-support parameter (the relative duration of all combined paws in contact with the glass floor), and base of support parameter (the average width of limb spreading between front or hind paws) were measured in ALS mice, and in all cases, the injection of miR126-5p improved all parameters respect to the control [126]. Based on these observations and previous reports, the authors suggested an attractive model of Sema3A/neuropilin-1 interaction that explains how the motor neuron degeneration in ALS could be regulated by miR126-5p. miR126-5p decrease in ALS could enhance Sema3A secretion in muscle and overexpression of neuropilin-1 in axons, increasing Sema3A signaling in the neuromuscular junction and leading to axon degeneration [126].

It is of consideration to test the results obtained with ALS mouse models in human samples. Motor cortex tissue samples showed increased Sema3A mRNA levels by quantitative RT-PCR in ALS patients (eight cases aged 44–72 years) compared to control samples (six subjects aged 45–84 years, with no neurological disease history). Likewise, by immunohistochemistry, the motor cortex showed stronger cytoplasmic and axonal Sema3A labeling in motor neurons of ALS patients compared to controls. Sema3A mRNA levels and immunohistological labeling showed, however, no difference between ALS patients and controls in spinal cord tissue samples [127]. Sema3A levels in human samples support the previous findings in ALS mouse models discussed above. However, other semaphorins and neurological factors not studied yet in the context of ALS may provide a better understanding of semaphorin function and mechanisms on ALS pathology.

#### **4.5 Spastic paraparesis associated to HTLV-1**

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is produced by infection with the retrovirus HTLV-1 (Human T-cell lymphotropic virus type 1 (HTLV-1) [128, 129]. HTLV-1 is transmitted by breast-feeding, sexual intercourse, and parenterally [130]. Worldwide, around 15–20 million people are infected with HTLV-1; however, only 3–5% develop HAM/TSP. Another ~5% develop adult T-cell leukemia/lymphoma (ATL), whereas over 90% of infected people are asymptomatic carriers [131]. The most common HAM/TSP symptom is lower limb motor dysfunction, followed with bladder/bowel dysfunctions and sensory alterations [132]. The virus mainly infects CD4+-T-cells, while monocytes, B-cells, CD8+-T-cells, and DC are infected to a lesser extent and found in spinal cord lesions together with infected astrocytes and endothelial cells [7, 133]. HAM/TSP causes alteration of CNS axonal transport based on the presence of APP deposits

**33**

*Roles of Semaphorins in Neurodegenerative Diseases DOI: http://dx.doi.org/10.5772/intechopen.82046*

CD8+-T-cells into the CNS [136].

patients and carriers [141].

pathological disturbances on neuronal cells.

signaling in oligodendrocytes during MS.

**4.6 Multiple sclerosis**

in the axons, a classical marker of defects in fast axonal transport [134, 135]. Immunological studies have shown a chronic infiltration of activated CD4+ and

It is a consensus that the paraparesis axonopathy generates as a consequence of chronic extracellular action of viral proteins secreted by the infected lymphocytes present in the CNS [137, 138]. Among secreted proteins, Tax viral protein acts on several viral and cellular processes, modulates various cellular signaling pathways, and has also been detected in the CSF of HAM/TSP patients. In the cytoplasm of infected lymphocytes, Tax activates NF-kB pathway responsible for proliferation and differentiation of T-cells, whereas in the nucleus, Tax activates the ATP/CREB pathway. Tax can also be secreted via endoplasmic reticulum-Golgi apparatus and by exosomes [136–141]. Tax secreted from activated peripheral blood mononuclear cells (PBMCs) could explain the presence of Tax in the plasma and CSF of infected

Using *in vitro* culture of PBMCs from HAM/TSP patients, it has been recently found that the levels of secreted Sema4D were increased compared to healthy subjects [142]. Elevated Sema4D could be explained as a result of increased levels of MT1-MMP—the enzyme responsible for generating soluble Sema4D (Sema4D) from the transmembrane Sema4D—found in PBMCs from HAM/TSP patients. It has been also found that Tax and SEMA4D co-immunoprecipitate from PBMC culture medium. To test the effect of Tax and Sema4D (or the Tax/Sema4D complex) in neuronal cells, culture media from infected lymphocytes were added to PC12 cells during their differentiation to neuronal type, finding decreased neurite length as a result. The effect of HTLV-1-infected PBMC culture media was blocked by both anti-Sema4D and anti-Tax antibodies, suggesting neurite length reduction by a Tax/Sema4D complex [142]. In the same report, it was shown that infected lymphocytes strongly migrate in response to Sema4D using a trans-well system. It was found that in the population of migrated lymphocytes, the levels of CRMP-2 phosphorylation at Ser522 were increased [142]. A change in Sema4Dmediated phosphorylation of CRMP-2 could be responsible for the increased motility. Authors proposed that infected lymphocytes have an increased migratory response toward Sema4D, making them able to cross the BBB [142]. Once in the CNS, infected lymphocytes secrete Tax and Sema4D, attracting more HTLV-1-infected lymphocytes at the same time that these proteins could mediate

MS is a CNS disease mostly considered of autoimmune etiology. It shows demyelinated plaques that sometimes remyelinate spontaneously. Remyelination involves the recruitment of OPC, which differentiate into mature oligodendrocytes in damaged areas to promote remyelination. Nevertheless, the remyelination process is prone to fail, leading to progressive disability [41, 143]. Even though there are multiple reports linking semaphorins with lymphocyte signaling during MS; in this section, we will focus on discussing the reports that have linked semaphorin

Sema3 proteins are the main semaphorins related to MS, although there is an increasing evidence of Sema4 involvement as well. Using postmortem human samples, the Lubetzki lab [144] showed the presence of numerous cells positive for Sema3A or Sema3F transcripts around and within demyelinating white matter lesions in MS brains, whereas these transcripts were absent in control adult brain white matter. The differential expression of Sema3A and Sema3F was strictly restricted to active plaques. No expression was detected in normal white matter

*Neurons - Dendrites and Axons*

binding to the 3′-untranslated region of target mRNAs [124]. The Perlson lab [125] analyzed miRNA profiles from axons and somas of two ALS mouse models, SOD1 with G93A mutation and TDP43 with A315T mutation. They showed that different miRNAs were significantly altered in the axons expressing ALS mutations, but not in the somas, indicating that miRNA could be regulating local functions in motor neuron axons [125]. Later, the same lab using qRT-PCR showed that one of these miRNAs, miR126-5p, downregulates Sema3A, Sema3B, neuropilin-1, and neuropilin-2 transcript levels in HeLa cells. Primary myoblasts with the SOD1G93A mutation were transfected with miR126-5p and cultured in a distal compartment of a microfluidic chamber together with a motor neuron explant placed in the proximal compartment. They showed that in the microfluidic chamber, the rate of axons that traversed the distal compartment was increased respect to the control condition of myoblasts transfected with an irrelevant miRNA. In addition, the injection of miR126-5p to ALS mice increased the amount of intact neuromuscular junctions revealing higher innervation in treated muscles compared to the mock condition. Three parameters: Mean Stand Index (measurement of the speed at which the paws detach from the walking surface), single-support parameter (the relative duration of all combined paws in contact with the glass floor), and base of support parameter (the average width of limb spreading between front or hind paws) were measured in ALS mice, and in all cases, the injection of miR126-5p improved all parameters respect to the control [126]. Based on these observations and previous reports, the authors suggested an attractive model of Sema3A/neuropilin-1 interaction that explains how the motor neuron degeneration in ALS could be regulated by miR126-5p. miR126-5p decrease in ALS could enhance Sema3A secretion in muscle and overexpression of neuropilin-1 in axons, increasing Sema3A signaling in the

neuromuscular junction and leading to axon degeneration [126].

semaphorin function and mechanisms on ALS pathology.

**4.5 Spastic paraparesis associated to HTLV-1**

It is of consideration to test the results obtained with ALS mouse models in human samples. Motor cortex tissue samples showed increased Sema3A mRNA levels by quantitative RT-PCR in ALS patients (eight cases aged 44–72 years) compared to control samples (six subjects aged 45–84 years, with no neurological disease history). Likewise, by immunohistochemistry, the motor cortex showed stronger cytoplasmic and axonal Sema3A labeling in motor neurons of ALS patients compared to controls. Sema3A mRNA levels and immunohistological labeling showed, however, no difference between ALS patients and controls in spinal cord tissue samples [127]. Sema3A levels in human samples support the previous findings in ALS mouse models discussed above. However, other semaphorins and neurological factors not studied yet in the context of ALS may provide a better understanding of

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is produced by infection with the retrovirus HTLV-1 (Human T-cell lymphotropic virus type 1 (HTLV-1) [128, 129]. HTLV-1 is transmitted by breast-feeding, sexual intercourse, and parenterally [130]. Worldwide, around 15–20 million people are infected with HTLV-1; however, only 3–5% develop HAM/TSP. Another ~5% develop adult T-cell leukemia/lymphoma (ATL), whereas over 90% of infected people are asymptomatic carriers [131]. The most common HAM/TSP symptom is lower limb motor dysfunction, followed with bladder/bowel dysfunctions and sensory alterations [132]. The virus mainly infects CD4+-T-cells, while monocytes, B-cells, CD8+-T-cells, and DC are infected to a lesser extent and found in spinal cord lesions together with infected astrocytes and endothelial cells [7, 133]. HAM/TSP causes alteration of CNS axonal transport based on the presence of APP deposits

**32**

in the axons, a classical marker of defects in fast axonal transport [134, 135]. Immunological studies have shown a chronic infiltration of activated CD4+ and CD8+-T-cells into the CNS [136].

It is a consensus that the paraparesis axonopathy generates as a consequence of chronic extracellular action of viral proteins secreted by the infected lymphocytes present in the CNS [137, 138]. Among secreted proteins, Tax viral protein acts on several viral and cellular processes, modulates various cellular signaling pathways, and has also been detected in the CSF of HAM/TSP patients. In the cytoplasm of infected lymphocytes, Tax activates NF-kB pathway responsible for proliferation and differentiation of T-cells, whereas in the nucleus, Tax activates the ATP/CREB pathway. Tax can also be secreted via endoplasmic reticulum-Golgi apparatus and by exosomes [136–141]. Tax secreted from activated peripheral blood mononuclear cells (PBMCs) could explain the presence of Tax in the plasma and CSF of infected patients and carriers [141].

Using *in vitro* culture of PBMCs from HAM/TSP patients, it has been recently found that the levels of secreted Sema4D were increased compared to healthy subjects [142]. Elevated Sema4D could be explained as a result of increased levels of MT1-MMP—the enzyme responsible for generating soluble Sema4D (Sema4D) from the transmembrane Sema4D—found in PBMCs from HAM/TSP patients. It has been also found that Tax and SEMA4D co-immunoprecipitate from PBMC culture medium. To test the effect of Tax and Sema4D (or the Tax/Sema4D complex) in neuronal cells, culture media from infected lymphocytes were added to PC12 cells during their differentiation to neuronal type, finding decreased neurite length as a result. The effect of HTLV-1-infected PBMC culture media was blocked by both anti-Sema4D and anti-Tax antibodies, suggesting neurite length reduction by a Tax/Sema4D complex [142]. In the same report, it was shown that infected lymphocytes strongly migrate in response to Sema4D using a trans-well system. It was found that in the population of migrated lymphocytes, the levels of CRMP-2 phosphorylation at Ser522 were increased [142]. A change in Sema4Dmediated phosphorylation of CRMP-2 could be responsible for the increased motility. Authors proposed that infected lymphocytes have an increased migratory response toward Sema4D, making them able to cross the BBB [142]. Once in the CNS, infected lymphocytes secrete Tax and Sema4D, attracting more HTLV-1-infected lymphocytes at the same time that these proteins could mediate pathological disturbances on neuronal cells.

#### **4.6 Multiple sclerosis**

MS is a CNS disease mostly considered of autoimmune etiology. It shows demyelinated plaques that sometimes remyelinate spontaneously. Remyelination involves the recruitment of OPC, which differentiate into mature oligodendrocytes in damaged areas to promote remyelination. Nevertheless, the remyelination process is prone to fail, leading to progressive disability [41, 143]. Even though there are multiple reports linking semaphorins with lymphocyte signaling during MS; in this section, we will focus on discussing the reports that have linked semaphorin signaling in oligodendrocytes during MS.

Sema3 proteins are the main semaphorins related to MS, although there is an increasing evidence of Sema4 involvement as well. Using postmortem human samples, the Lubetzki lab [144] showed the presence of numerous cells positive for Sema3A or Sema3F transcripts around and within demyelinating white matter lesions in MS brains, whereas these transcripts were absent in control adult brain white matter. The differential expression of Sema3A and Sema3F was strictly restricted to active plaques. No expression was detected in normal white matter

distant to active lesions, around/within chronically demyelinated lesions or remyelinated plaques [144]. Later, also in human MS tissue samples, it was shown that although the chemoattractant Sema3F and chemorepellent Sema3A had similar protein expression patterns in some lesions, Sema3A was predominantly expressed in chronic active lesions, which mostly contain few OPCs [145].

The Lubetzki lab [42] also used a mouse model where demyelinated lesions are induced by lysophosphatidylcholine injection. They found that adult OPCs express Sema3 receptors (plexin A and neuropilin 1 and 2) and that the expression of these receptors, together with Sema3A and Sema3F, is increased after the induction of lesions. Interestingly, *in vivo* lentiviral expression of Sema3A decreased the OPC density in induced lesions, whereas Sema3F produced the opposite effect. When a transgenic mouse with a mutated NRP1 preventing Sema3A binding was used, an increase in OPC density was found after the induction of lesions compared to wildtype mice. The density of remyelinated axons increased in lesions of animals receiving the Sema3F, but not the Sema3A lentiviral vector [42]. Using a similar approach, in a more recent publication 145, the authors injected recombinant Sema3A and Sema3F to mice. Sema3A-treated mice had significantly fewer OPCs on the side of the lesion compared to the opposite side without lesion, whereas Sema3F-treated mice had increased number of OPCs in the lesion side [145]. Parallel studies in rats have shown that Sema3A inhibits CNS remyelination and the lineage progression of OPCs in demyelinated lesions, arresting OPCs at a premyelinating state [44]. Finally, a recent report using exome sequencing analysis found an association of a missense mutation in the *plexin A3* gene (receptor of Sema3A and Sema3F) with increased disability in MS males. Given the gender association, the authors debated whether the *plexin A3* mutation could alter the protein stability, interfering with its ligand binding and arguing the possibility of protective effects of estradiol in females [146]. Considering that in MS lesions, Sema3A and its receptors are also expressed in neurons, reactive astrocytes, and microglia/macrophages [147], the source of Sema3A can be multiple and simultaneously affect not only OPCs signaling, but also other cell types.

There are also some reports linking MS with Sema4. Ferritin uptake by oligodendrocytes is mediated by the Tim2 receptor and required for iron acquisition. In addition to ferritin, Tim2 binds Sema4A [148]. Recombinant Sema4A exposure to primary rat OPCs resulted in dose-dependent OPC cytotoxicity. Astrocytes and mature oligodendrocytes were, however, unaffected. The authors suggested that the observed cytotoxicity could be mediated by Tim2 receptor. Lymphocytes, macrophages, or microglia could be the source of Sema4A *in vivo* [149]. Later, the same group found that human oligodendrocytes undergo apoptosis when exposed to Sema4A and that the levels of this protein are increased in multiple sclerosis patients [150]. A different research group used recombinant Sema4D in an *in vitro* model of cultured OPC, resulting in actin filament rearrangement indicative of cytoskeletal collapse, along with an increase in apoptotic cells and fewer OPC differentiating into mature oligodendrocytes. All these effects were avoided by incubation with anti-Sema4D antibody [39]. The relative contribution of different semaphorins remains to be tested in future experiments in order to understand their role in the nervous system during MS.

#### **4.7 Cross talk between the immune and the nervous systems**

Even though the semaphorin signaling in lymphocytes is not the main subject of this chapter, it is impossible to completely dissociate the semaphorin signaling

**35**

*Roles of Semaphorins in Neurodegenerative Diseases DOI: http://dx.doi.org/10.5772/intechopen.82046*

**5. Conclusion and future perspectives**

contribute to future therapeutic strategies.

during EAE [151–153].

these cells.

in the nervous system from their roles in the immune system. The cross talk between these systems is extensive, and different neurological disorders are considered to have an important neuroinflammatory component. For example, the most commonly used animal model for MS is the experimental autoimmune encephalomyelitis (EAE) model, which resembles neuroinflammatory conditions. Different authors suggest that the effect of semaphorins in the nervous system is most likely an indirect effect through modulation of the neuroinflammation produced by immune cells in the nervous system, supported by using the EAE model. For instance, the EAE pathology is exacerbated in Sema7Adeficient mice, and T cells are hyperactive in response to activation in this model. Similarly, Sema4A is increased in MS patients and associated to nonresponsiveness to IFN-β therapy. Anti-Sema4D antibodies inhibited neuroinflammation

Most of the patients who later will develop MS, usually, have an acute episode of neurological disturbance known as clinically isolated syndrome (CIS). The Montalban lab [154], using mass-spectrometry analysis, identified proteins associated with conversion to MS in CSF samples from CIS patients in a follow-up study. They found that Sema7A was downregulated in patients who later converted to MS [154, 155]. Using the EAE model, the same group found that Sema3A is increased in the CNS and decreased in the immune system, whereas Sema7A is increased in both systems [156]. The above results suggest an intricated system where different semaphorins can be participating at the same time. It is important to understand the relative contribution of different neuronal types and different immune cell types to the pathology and also the amount of soluble semaphorins available to interact with

Throughout this chapter, we have reviewed the currently known implications of different semaphorin classes to some relevant neurological disorders, highlighting their receptors and signaling pathways that could be affected in neuropathologies. Even though the diseases we discussed here represent just a fraction among several other semaphorin-affected neurodegenerative, psychiatric, and immunological disorders, they are also likely representative of the semaphorin function. The advances so far in this field are promising, yet the results obtained from murine systems require testing on human models and subsequently, approaching to eventual therapies and clinical trials. We have already mentioned the potential of semaphorins for cell replacement therapy, such as in the recent approaches on PD [105], or the alternative new drug developments to target specific semaphorininduced kinases, such as in AD [67]. All these new treatment alternatives emerged in the recent years from the advances in understanding semaphorin-mediated mechanisms on human diseases. In addition, semaphorins have been recently pointed as the center for new therapeutic strategies using blocking antibodies. For example, the VX15/2503, an anti-Sema4D antibody has been characterized for clinical development on MS, Huntington's disease, and cancer [157]. LaGanke et al. carried out a phase 1 study providing evidence that the VX15/2503 antisemaphorin 4D antibody administered at various doses was safe and tolerated in patients with MS [158]. It is expected in following years that new breakthroughs will further highlight semaphorin function in neurodegenerative conditions and

*Neurons - Dendrites and Axons*

ing, but also other cell types.

distant to active lesions, around/within chronically demyelinated lesions or remyelinated plaques [144]. Later, also in human MS tissue samples, it was shown that although the chemoattractant Sema3F and chemorepellent Sema3A had similar protein expression patterns in some lesions, Sema3A was predominantly expressed

The Lubetzki lab [42] also used a mouse model where demyelinated lesions are induced by lysophosphatidylcholine injection. They found that adult OPCs express Sema3 receptors (plexin A and neuropilin 1 and 2) and that the expression of these receptors, together with Sema3A and Sema3F, is increased after the induction of lesions. Interestingly, *in vivo* lentiviral expression of Sema3A decreased the OPC density in induced lesions, whereas Sema3F produced the opposite effect. When a transgenic mouse with a mutated NRP1 preventing Sema3A binding was used, an increase in OPC density was found after the induction of lesions compared to wildtype mice. The density of remyelinated axons increased in lesions of animals receiving the Sema3F, but not the Sema3A lentiviral vector [42]. Using a similar approach, in a more recent publication 145, the authors injected recombinant Sema3A and Sema3F to mice. Sema3A-treated mice had significantly fewer OPCs on the side of the lesion compared to the opposite side without lesion, whereas Sema3F-treated mice had increased number of OPCs in the lesion side [145]. Parallel studies in rats have shown that Sema3A inhibits CNS remyelination and the lineage progression of OPCs in demyelinated lesions, arresting OPCs at a premyelinating state [44]. Finally, a recent report using exome sequencing analysis found an association of a missense mutation in the *plexin A3* gene (receptor of Sema3A and Sema3F) with increased disability in MS males. Given the gender association, the authors debated whether the *plexin A3* mutation could alter the protein stability, interfering with its ligand binding and arguing the possibility of protective effects of estradiol in females [146]. Considering that in MS lesions, Sema3A and its receptors are also expressed in neurons, reactive astrocytes, and microglia/macrophages [147], the source of Sema3A can be multiple and simultaneously affect not only OPCs signal-

There are also some reports linking MS with Sema4. Ferritin uptake by oligodendrocytes is mediated by the Tim2 receptor and required for iron acquisition. In addition to ferritin, Tim2 binds Sema4A [148]. Recombinant Sema4A exposure to primary rat OPCs resulted in dose-dependent OPC cytotoxicity. Astrocytes and mature oligodendrocytes were, however, unaffected. The authors suggested that the observed cytotoxicity could be mediated by Tim2 receptor. Lymphocytes, macrophages, or microglia could be the source of Sema4A *in vivo* [149]. Later, the same group found that human oligodendrocytes undergo apoptosis when exposed to Sema4A and that the levels of this protein are increased in multiple sclerosis patients [150]. A different research group used recombinant Sema4D in an *in vitro* model of cultured OPC, resulting in actin filament rearrangement indicative of cytoskeletal collapse, along with an increase in apoptotic cells and fewer OPC differentiating into mature oligodendrocytes. All these effects were avoided by incubation with anti-Sema4D antibody [39]. The relative contribution of different semaphorins remains to be tested in future experiments in order to understand their role in the nervous

Even though the semaphorin signaling in lymphocytes is not the main subject of this chapter, it is impossible to completely dissociate the semaphorin signaling

**4.7 Cross talk between the immune and the nervous systems**

in chronic active lesions, which mostly contain few OPCs [145].

**34**

system during MS.

in the nervous system from their roles in the immune system. The cross talk between these systems is extensive, and different neurological disorders are considered to have an important neuroinflammatory component. For example, the most commonly used animal model for MS is the experimental autoimmune encephalomyelitis (EAE) model, which resembles neuroinflammatory conditions. Different authors suggest that the effect of semaphorins in the nervous system is most likely an indirect effect through modulation of the neuroinflammation produced by immune cells in the nervous system, supported by using the EAE model. For instance, the EAE pathology is exacerbated in Sema7Adeficient mice, and T cells are hyperactive in response to activation in this model. Similarly, Sema4A is increased in MS patients and associated to nonresponsiveness to IFN-β therapy. Anti-Sema4D antibodies inhibited neuroinflammation during EAE [151–153].

Most of the patients who later will develop MS, usually, have an acute episode of neurological disturbance known as clinically isolated syndrome (CIS). The Montalban lab [154], using mass-spectrometry analysis, identified proteins associated with conversion to MS in CSF samples from CIS patients in a follow-up study. They found that Sema7A was downregulated in patients who later converted to MS [154, 155]. Using the EAE model, the same group found that Sema3A is increased in the CNS and decreased in the immune system, whereas Sema7A is increased in both systems [156]. The above results suggest an intricated system where different semaphorins can be participating at the same time. It is important to understand the relative contribution of different neuronal types and different immune cell types to the pathology and also the amount of soluble semaphorins available to interact with these cells.

#### **5. Conclusion and future perspectives**

Throughout this chapter, we have reviewed the currently known implications of different semaphorin classes to some relevant neurological disorders, highlighting their receptors and signaling pathways that could be affected in neuropathologies. Even though the diseases we discussed here represent just a fraction among several other semaphorin-affected neurodegenerative, psychiatric, and immunological disorders, they are also likely representative of the semaphorin function. The advances so far in this field are promising, yet the results obtained from murine systems require testing on human models and subsequently, approaching to eventual therapies and clinical trials. We have already mentioned the potential of semaphorins for cell replacement therapy, such as in the recent approaches on PD [105], or the alternative new drug developments to target specific semaphorininduced kinases, such as in AD [67]. All these new treatment alternatives emerged in the recent years from the advances in understanding semaphorin-mediated mechanisms on human diseases. In addition, semaphorins have been recently pointed as the center for new therapeutic strategies using blocking antibodies. For example, the VX15/2503, an anti-Sema4D antibody has been characterized for clinical development on MS, Huntington's disease, and cancer [157]. LaGanke et al. carried out a phase 1 study providing evidence that the VX15/2503 antisemaphorin 4D antibody administered at various doses was safe and tolerated in patients with MS [158]. It is expected in following years that new breakthroughs will further highlight semaphorin function in neurodegenerative conditions and contribute to future therapeutic strategies.

*Neurons - Dendrites and Axons*

### **Author details**

Sebastian Quintremil1† , Fernando Medina Ferrer1,2† , Javier Puente1 , María Elsa Pando1 and María Antonieta Valenzuela1 \*

1 Department of Biochemistry and Molecular Biology, College of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile

2 Department of Earth Sciences, University of Minnesota, Minneapolis, Minnesota, USA

\*Address all correspondence to: mavalenz@uchile.cl

† Authors contributed equally to this work.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**37**

*Roles of Semaphorins in Neurodegenerative Diseases DOI: http://dx.doi.org/10.5772/intechopen.82046*

[1] Alto LT, Terman JR. Semaphorins and their signaling mechanisms. Methods in Molecular Biology. 2017;**1493**:1-25. DOI:

[9] Yazdani U, Terman JR. The semaphorins. Genome Biology. 2006;**7**:211. DOI: 10.1186/

[10] Roney K, Holl E, Ting J. Immune plexins and semaphorins: Old proteins, new immune functions. Protein & Cell. 2013;**4**:17-26. DOI: 10.1007/

[11] Yoshida Y. Semaphorin signaling

[12] Zhou Y, Gunput RA, Pasterkamp RJ.

Semaphorin signaling: Progress made and promises ahead. Trends in Biochemical Sciences. 2008;**33**:161-170.

DOI: 10.1016/j.tibs.2008.01.006

[13] Sharma A, Verhaagen J, Harvey AR. Receptor complexes for each of the Class 3 Semaphorins. Frontiers in Cellular Neuroscience. 2012;**6**:28. DOI: 10.3389/fncel.2012.00028. eCollection

[14] Takamatsu H, Kumanogoh A. Diverse roles for semaphorin-plexin signaling in the immune system. Trends in Immunology. 2012;**33**:127-135. DOI:

[15] Pasterkamp RJ. Getting neural circuits into shape with semaphorins. Nature Reviews. Neuroscience.

2012;**13**:605-618. DOI: 10.1038/nrn3302

[16] Tillo M, Ruhrberg C, Mackenzie F. Emerging roles for semaphorins and VEGFs in synaptogenesis and synaptic plasticity. Cell Adhesion & Migration.

2012;**6**:541-546. DOI: 10.4161/

[17] Sarabipour S, Mac Gabhann F. VEGF-A121a binding to Neuropilins-A concept revisited. Cell Adhesion &

cam.22408

10.1016/j.it.2012.01.008

in vertebrate neural circuit assembly. Frontiers in Molecular Neuroscience. 2012;**5**:71. DOI: 10.3389/

gb-2006-7-3-211

s13238-012-2108-4

fnmol.2012.00071

2012

[2] Pasterkamp RJ, Giger RJ. Semaphorin function in neural plasticity and disease. Current Opinion in Neurobiology. 2009;**19**:263-274. DOI: 10.1016/j.

[3] Okuno T, Nakatsuji Y, Kumanogoh A. The role of immune semaphorins in multiple sclerosis. FEBS Letters. 2011;**585**:3829-3835. DOI: 10.1016/j.

Verhaagen J. A perspective on the role of Class III semaphorin signaling in central nervous system trauma. Frontiers in Cellular Neuroscience. 2014;**8**:328. DOI:

Pasterkamp RJ. Axon guidance proteins in neurological disorders. Lancet Neurology. 2015;**14**:532-546. DOI: 10.1016/S1474-4422(14)70257-1

10.1007/978-1-4939-6448-2 1

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#### **References**

*Neurons - Dendrites and Axons*

**36**

USA

†

**Author details**

María Elsa Pando1

Sebastian Quintremil1†

provided the original work is properly cited.

Authors contributed equally to this work.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

, Fernando Medina Ferrer1,2†

1 Department of Biochemistry and Molecular Biology, College of Chemical and

2 Department of Earth Sciences, University of Minnesota, Minneapolis, Minnesota,

and María Antonieta Valenzuela1

Pharmaceutical Sciences, University of Chile, Santiago, Chile

\*Address all correspondence to: mavalenz@uchile.cl

, Javier Puente1

\*

,

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[3] Okuno T, Nakatsuji Y, Kumanogoh A. The role of immune semaphorins in multiple sclerosis. FEBS Letters. 2011;**585**:3829-3835. DOI: 10.1016/j. febslet.2011.03.033

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[5] Van Battum EY, Brignani S, Pasterkamp RJ. Axon guidance proteins in neurological disorders. Lancet Neurology. 2015;**14**:532-546. DOI: 10.1016/S1474-4422(14)70257-1

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[8] Gitler AD, Dhillon P, Shorter J. Neurodegenerative disease: Models, mechanisms, and a new hope. Disease Models & Mechanisms. 2017;**10**: 499-502. DOI: 10.1242/dmm.030205

[9] Yazdani U, Terman JR. The semaphorins. Genome Biology. 2006;**7**:211. DOI: 10.1186/ gb-2006-7-3-211

[10] Roney K, Holl E, Ting J. Immune plexins and semaphorins: Old proteins, new immune functions. Protein & Cell. 2013;**4**:17-26. DOI: 10.1007/ s13238-012-2108-4

[11] Yoshida Y. Semaphorin signaling in vertebrate neural circuit assembly. Frontiers in Molecular Neuroscience. 2012;**5**:71. DOI: 10.3389/ fnmol.2012.00071

[12] Zhou Y, Gunput RA, Pasterkamp RJ. Semaphorin signaling: Progress made and promises ahead. Trends in Biochemical Sciences. 2008;**33**:161-170. DOI: 10.1016/j.tibs.2008.01.006

[13] Sharma A, Verhaagen J, Harvey AR. Receptor complexes for each of the Class 3 Semaphorins. Frontiers in Cellular Neuroscience. 2012;**6**:28. DOI: 10.3389/fncel.2012.00028. eCollection 2012

[14] Takamatsu H, Kumanogoh A. Diverse roles for semaphorin-plexin signaling in the immune system. Trends in Immunology. 2012;**33**:127-135. DOI: 10.1016/j.it.2012.01.008

[15] Pasterkamp RJ. Getting neural circuits into shape with semaphorins. Nature Reviews. Neuroscience. 2012;**13**:605-618. DOI: 10.1038/nrn3302

[16] Tillo M, Ruhrberg C, Mackenzie F. Emerging roles for semaphorins and VEGFs in synaptogenesis and synaptic plasticity. Cell Adhesion & Migration. 2012;**6**:541-546. DOI: 10.4161/ cam.22408

[17] Sarabipour S, Mac Gabhann F. VEGF-A121a binding to Neuropilins-A concept revisited. Cell Adhesion &

Migration. 2018;**12**:204-214. DOI: 10.1080/19336918.2017.1372878

[18] Kimura T, Watanabe H, Iwamatsu A, Kaibuchi K. Tubulin and CRMP-2 complex is transported via Kinesin-1. Journal of Neurochemistry. 2005;**93**:1371-1382. DOI: 10.1111/j.1471-4159.2005.03063.x

[19] Schmidt EF, Strittmatter SM. The CRMP family of proteins and their role in Sema3A signaling. Advances in Experimental Medicine and Biology. 2007;**600**:1-11. DOI: 10.1007/978-0-387-70956-7\_1

[20] Chae YC, Lee S, Heo K, Ha SH, Jung Y, Kim JH, et al. Collapsin response mediator protein-2 regulates neurite formation by modulating tubulin GTPase activity. Cellular Signalling. 2009;**21**:1818-1826. DOI: 10.1016/j. cellsig.2009.07.017

[21] Hensley K, Venkova K, Christov A, Gunning W, Park J. Collapsin response mediator protein-2: An emerging pathologic feature and therapeutic target for neurodisease indications. Molecular Neurobiology. 2011;**43**:180-191. DOI: 10.1007/s12035-011-8166-4

[22] Khanna R, Wilson SM, Brittain JM, Weimer J, Sultana R, Butterfield A, et al. Opening Pandora's jar: A primer on the putative roles of CRMP2 in a panoply of neurodegenerative, sensory and motor neuron, and central disorders. Future Neurology. 2012;**7**:749-771. DOI: 10.2217/FNL.12.68

[23] Brown JA, Bridgman PC. Disruption of the cytoskeleton during Semaphorin 3A induced growth cone collapse correlates with differences in actin organization and associated binding proteins. Developmental Neurobiology. 2009;**69**:633-646. DOI: 10.1002/ dneu.20732

[24] Oinuma I, Ito Y, Katoh H, Negishi M. Semaphorin 4D/Plexin-B1 stimulates PTEN activity through R-Ras GTPaseactivating protein activity, inducing growth cone collapse in hippocampal neurons. The Journal of Biological Chemistry. 2010;**285**:28200-28209. DOI: 10.1074/jbc.M110.147546

[25] Gallo G. RhoA-kinase coordinates F-actin organization and myosin II activity during semaphorin-3A-induced axon retraction. Journal of Cell Science. 2006;**119**:3413-3423. DOI: 10.1242/ jcs.03084

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[27] Vodrazka P, Korostylev A, Hirschberg A, Swiercz JM, Worzfeld T, Deng S, et al. The semaphorin 4D-plexin-B signalling complex regulates dendritic and axonal complexity in developing neurons via diverse pathways. The European Journal of Neuroscience. 2009;**30**:1193-1208. DOI: 10.1111/j.1460-9568.2009.06934.x

[28] McDermott JE, Goldblatt D, Paradis S. Class 4 Semaphorins and Plexin-B receptors regulate GABAergic and glutamatergic synapse development in the mammalian hippocampus. Molecular and Cellular Neurosciences. 2018;**92**:50-66. DOI: 10.1016/j. mcn.2018.06.008

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microglia, and inhibits remyelination

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[35] Anderson JE, Do MQ, Daneshvar N, Suzuki T, Dort J, Mizunoya W, et al. The role of semaphorin3A in myogenic regeneration and the formation of functional neuromuscular junctions on new fibres. Biological Reviews of the Cambridge Philosophical Society. 2017;**92**:1389-1405. DOI: 10.1111/

[36] Peng SX, Yao L, Cui C, Zhao HD, Liu CJ, Li YH, et al. Semaphorin4D promotes axon regrowth and swimming ability during recovery following zebrafish spinal cord injury. Neuroscience. 2017;**351**:36-46. DOI: 10.1016/j.neuroscience.2017.03.030

pone.0191962. eCollection 2018

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regeneration. Glia. 2004;**46**:225-251. DOI: 10.1002/glia.10315

*Neurons - Dendrites and Axons*

A, Kaibuchi K. Tubulin and

2005;**93**:1371-1382. DOI:

cellsig.2009.07.017

10.1007/s12035-011-8166-4

10.2217/FNL.12.68

Migration. 2018;**12**:204-214. DOI: 10.1080/19336918.2017.1372878

[18] Kimura T, Watanabe H, Iwamatsu

PTEN activity through R-Ras GTPaseactivating protein activity, inducing growth cone collapse in hippocampal neurons. The Journal of Biological Chemistry. 2010;**285**:28200-28209. DOI:

[25] Gallo G. RhoA-kinase coordinates F-actin organization and myosin II activity during semaphorin-3A-induced axon retraction. Journal of Cell Science. 2006;**119**:3413-3423. DOI: 10.1242/

[26] Dent EW, Gupton SL, Gertler FB. The growth cone cytoskeleton in axon outgrowth and guidance. Cold Spring Harbor Perspectives in Biology. 2011;**3**:1-39. pii: a001800. DOI: 10.1101/

10.1074/jbc.M110.147546

cshperspect.a001800

[27] Vodrazka P, Korostylev A, Hirschberg A, Swiercz JM, Worzfeld T, Deng S, et al. The semaphorin 4D-plexin-B signalling complex regulates dendritic and axonal complexity in developing neurons via diverse pathways. The European Journal of Neuroscience.

2009;**30**:1193-1208. DOI:

10.1111/j.1460-9568.2009.06934.x

2018;**92**:50-66. DOI: 10.1016/j.

10.1017/S1462399409001288

[30] Sandvig A, Berry M, Barrett LB, Butt A, Logan A. Myelin-, reactive glia-, and scar-derived CNS axon growth inhibitors: Expression, receptor signaling, and correlation with axon

mcn.2018.06.008

[28] McDermott JE, Goldblatt D, Paradis S. Class 4 Semaphorins and Plexin-B receptors regulate GABAergic and glutamatergic synapse development in the mammalian hippocampus. Molecular and Cellular Neurosciences.

[29] Afshari FT, Kappagantula S, Fawcett JW. Extrinsic and intrinsic factors controlling axonal regeneration after spinal cord injury. Expert Reviews in Molecular Medicine. 2009;**11**:e37. DOI:

jcs.03084

CRMP-2 complex is transported via Kinesin-1. Journal of Neurochemistry.

10.1111/j.1471-4159.2005.03063.x

[19] Schmidt EF, Strittmatter SM. The CRMP family of proteins and their role in Sema3A signaling. Advances in Experimental Medicine and Biology. 2007;**600**:1-11. DOI: 10.1007/978-0-387-70956-7\_1

[20] Chae YC, Lee S, Heo K, Ha SH, Jung Y, Kim JH, et al. Collapsin response mediator protein-2 regulates neurite formation by modulating tubulin GTPase activity. Cellular Signalling. 2009;**21**:1818-1826. DOI: 10.1016/j.

[21] Hensley K, Venkova K, Christov A, Gunning W, Park J. Collapsin response mediator protein-2: An emerging

pathologic feature and therapeutic target for neurodisease indications. Molecular Neurobiology. 2011;**43**:180-191. DOI:

[22] Khanna R, Wilson SM, Brittain JM, Weimer J, Sultana R, Butterfield A, et al. Opening Pandora's jar: A primer on the putative roles of CRMP2 in a panoply of neurodegenerative, sensory and motor neuron, and central disorders. Future Neurology. 2012;**7**:749-771. DOI:

[23] Brown JA, Bridgman PC. Disruption of the cytoskeleton during Semaphorin 3A induced growth cone collapse correlates with differences in actin organization and associated binding proteins. Developmental Neurobiology.

2009;**69**:633-646. DOI: 10.1002/

[24] Oinuma I, Ito Y, Katoh H, Negishi M. Semaphorin 4D/Plexin-B1 stimulates

**38**

dneu.20732

[31] Bolsover S, Fabes J, Anderson PN. Axonal guidance molecules and the failure of axonal regeneration in the adult mammalian spinal cord. Restorative Neurology and Neuroscience. 2008;**26**:117-130

[32] McCormick AM, Leipzig ND. Neural regenerative strategies incorporating biomolecular axon guidance signals. Annals of Biomedical Engineering. 2012;**40**:578-597. DOI: 10.1007/s10439-011-0505-0

[33] Shim SO, Cafferty WB, Schmidt EC, Kim BG, Fujisawa H, Strittmatter SM. PlexinA2 limits recovery from corticospinal axotomy by mediating oligodendrocyte-derived Sema6A growth inhibition. Molecular and Cellular Neurosciences. 2012;**50**: 193-200. DOI: 10.1016/j.mcn. 2012.04.007

[34] Zhang M, Zhou Q, Luo Y, Nguyen T, Rosenblatt MI, Guaiquil VH. Semaphorin3A induces nerve regeneration in the adult cornea-a switch from its repulsive role in development. PLoS One. 2018;**13**:e0191962. DOI: 10.1371/journal. pone.0191962. eCollection 2018

[35] Anderson JE, Do MQ, Daneshvar N, Suzuki T, Dort J, Mizunoya W, et al. The role of semaphorin3A in myogenic regeneration and the formation of functional neuromuscular junctions on new fibres. Biological Reviews of the Cambridge Philosophical Society. 2017;**92**:1389-1405. DOI: 10.1111/ brv.12286

[36] Peng SX, Yao L, Cui C, Zhao HD, Liu CJ, Li YH, et al. Semaphorin4D promotes axon regrowth and swimming ability during recovery following zebrafish spinal cord injury. Neuroscience. 2017;**351**:36-46. DOI: 10.1016/j.neuroscience.2017.03.030

[37] Sakurai A, Doçi CL, Gutkind JS. Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer. Cell Research. 2012;**22**:23-32. DOI: 10.1038/ cr.2011.198

[38] Oh WJ, Gu C. The role and mechanism-of-action of Sema3E and Plexin-D1 in vascular and neural development. Seminars in Cell & Developmental Biology. 2013;**24**: 156-162. DOI: 10.1016/j. semcdb.2012.12.001

[39] Smith ES, Jonason A, Reilly C, Veeraraghavan J, Fisher T, Doherty M, et al. SEMA4D compromises blood-brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease. Neurobiology of Disease. 2015;**73**: 254-268. DOI: 10.1016/j.nbd. 2014.10.008

[40] Basile JR, Gavard J, Gutkind JS. Plexin-B1 utilizes RhoA and Rho kinase to promote the integrindependent activation of Akt and ERK and endothelial cell motility. The Journal of Biological Chemistry. 2007;**282**:34888-34895. DOI: 10.1074/ jbc.M705467200

[41] Franklin RJ, Ffrench-Constant C. Remyelination in the CNS: From biology to therapy. Nature Reviews. Neuroscience. 2008;**9**:839-855. DOI: 10.1038/nrn2480

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[43] Alizadeh A, Dyck SM, Karimi-Abdolrezaee S. Myelin damage and repair in pathologic CNS: Challenges and prospects. Frontiers in Molecular Neuroscience. 2015;**8**:35. DOI: 10.3389/ fnmol.2015.00035

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JNEUROSCI.3184-04.2004

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10.1038/376509a0

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10.1016/j.mcn.2011.12.004

10.1098/rstb.2005.1696

s12026-010-8201-y

fnint.2013.00064

SP. Biology and function of neuroimmune semaphorins 4A and 4D. Immunologic Research. 2011;**50**:10-21. DOI: 10.1007/

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[47] Nkyimbeng-Takwi E, Chapoval

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[49] Chavarría A, Cárdenas G. Neuronal influence behind the central nervous system regulation of the immune cells. Frontiers in Integrative

Neuroscience. 2013;**7**:64. DOI: 10.3389/

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[51] Pellet-Many C, Frankel P, Jia H, Zachary I. Neuropilins: Structure,

DOI: 10.1016/j.it.2008.11.002

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function and role in disease.

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gene.2017.02.013

JNR4>3.0.CO;2-M

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Biochemical Journal. 2008;**411**:211-226.

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**40**

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[64] Uchida Y, Ohshima T, Sasaki Y, Suzuki H, Yanai S, Yamashita N, et al. Semaphorin3A signalling is mediated via sequential Cdk5 and GSK3beta phosphorylation of CRMP2: Implication of common phosphorylating mechanism underlying axon guidance and Alzheimer's disease. Genes to Cells. 2005;**10**:165-179. DOI: 10.1111/j.1365-2443.2005.00827.x

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*Neurons - Dendrites and Axons*

jbc.M111.310029

2013;**10**:809-817

perineuronal nets via chondroitin sulfate type E motifs in rodent brains. The Journal of Biological Chemistry. 2013;**288**:27384-27395. DOI: 10.1074/

[78] Shirvan A, Shina R, Ziv I, Melamed E, Barzilai A. Induction of neuronal apoptosis by Semaphorin3A-derived peptide. Brain Research. Molecular Brain Research. 2000;**83**:81-93

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[84] Elbaz A, Nelson LM, Payami H, Ioannidis JPA, Fiske BK, Annesi G, et al. Lack of replication of thirteen singlenucleotide polymorphisms implicated in Parkinson's disease: A large-scale international study. Lancet Neurology.

2006;**5**:917-923. DOI: 10.1016/ S1474-4422(06)70579-8

2000;**60**:59-76

2003;**91**:73-82

DOI: 10.1002/ana.20228

10.1086/496902

[71] Moreno-Flores MT, Martín-Aparicio E, Martín-Bermejo MJ, Agudo M, McMahon S, Avila J, et al. Semaphorin 3C preserves survival and induces neuritogenesis of cerebellar granule neurons in culture. Journal of Neurochemistry. 2003;**87**:879-890

[72] Hauser PS, Ryan RO. Impact of apolipoprotein E on Alzheimer's disease. Current Alzheimer Research.

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[74] Ueki M, Kawasaki Y, Tamiya G. For Alzheimer's disease neuroimaging initiative. Detecting genetic association through shortest paths in a bidirected

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graph. Genetic Epidemiology. 2017;**41**:481-497. DOI: 10.1002/

10.1016/j.jalz.2016.01.010

[76] Tysnes O-B, Storstein A.

Epidemiology of Parkinson's disease. Journal of Neural Transmission (Vienna). 2017;**124**:901-905. DOI: 10.1007/s00702-017-1686-y

[77] Shirvan A, Ziv I, Fleminger G, Shina R, He Z, Brudo I, et al.

Semaphorins as mediators of neuronal apoptosis. Journal of Neurochemistry.

gepi.22051

**42**

1999;**73**:961-971

[85] Clarimon J, Scholz S, Fung H-C, Hardy J, Eerola J, Hellstrom O, et al. Conflicting results regarding the semaphorin gene (SEMA5A) and the risk for Parkinson disease. American Journal of Human Genetics. 2006;**78**:1082-1084; author reply 1092- 1094. DOI: 10.1086/504727

[86] Ding H, Wang F, Ding X, Song X, Lu X, Zhang K, et al. Association study of semaphorin 5A with risk of Parkinson's disease in a Chinese Han population. Brain Research. 2008;**1245**:126-129. DOI: 10.1016/j. brainres.2008.09.080

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[124] Haidar M, Rchiad Z, Ansari HR, Ben-Rached F, Tajeri S, Latre De Late P, et al. miR-126-5p by direct targeting of JNK-interacting protein-2 (JIP-2) plays a key role in Theileria-infected macrophage virulence. PLoS Pathogens. 2018;**14**:e1006942. DOI: 10.1371/journal.

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[126] Maimon R, Ionescu A, Bonnie A, Sweetat S, Wald-Altman S, Inbar S, et al. miR126-5p downregulation facilitates axon degeneration and NMJ disruption via a non-cell-autonomous mechanism in ALS. The Journal of Neuroscience. 2018;**38**:5478-5494. DOI: 10.1523/

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Knippenberg S, et al. The axon guidance protein Semaphorin 3A is increased in the motor cortex of patients with amyotrophic lateral sclerosis. Journal of Neuropathology and Experimental Neurology. 2016;**75**:326-333. pii: nlw003.

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[137] Cartier L, Ramirez E. Presence of HTLV-I tax protein in cerebrospinal fluid from HAM/TSP patients. Archives of Virology. 2005;**150**:743-753. DOI: 10.1007/s00705-004-0443-3

[138] Jain P, Ahuja J, Khan ZK, Shimizu S, Meucci O, Jennings SR, et al. Modulation of dendritic cell maturation and function by the tax protein of human T cell leukemia virus type 1. Journal of Leukocyte Biology. 2007;**82**:44-56. DOI: 10.1189/ jlb.1006641

[139] Alefantis T, Jain P, Ahuja J, Mostoller K, Wigdahl B. HTLV-1 tax nucleocytoplasmic shuttling, interaction with the secretory pathway, extracellular signaling, and implications for neurologic disease. Journal of Biomedical Science. 2005;**12**:961-974. DOI: 10.1007/s11373-005-9026-x

[140] Medina F, Quintremil S, Alberti C, Barriga A, Cartier L, Puente J, et al. Tax posttranslational modifications and interaction with calreticulin in MT-2 cells and human peripheral blood mononuclear cells of human T cell lymphotropic virus type-I-associated myelopathy/tropical spastic paraparesis patients. AIDS Research and Human Retroviruses. 2014;**30**:370-379. DOI: 10.1089/AID.2013.0036

[141] Medina F, Quintremil S, Alberti C, Godoy F, Pando ME, Bustamante A, et al. Tax secretion from peripheral blood mononuclear cells and tax detection in plasma of patients with human T-lymphotropic virus-type 1-associated myelopathy/tropical

spastic paraparesis and asymptomatic carriers. Journal of Medical Virology. 2016;**88**:521-531. DOI: 10.1002/ jmv.24342

[142] Quintremil S, Alberti C, Rivera M, Medina F, Puente J, Cartier L, et al. Tax and Semaphorin 4D released from lymphocytes infected with human lymphotropic virus type 1 and their effect on neurite growth. AIDS Research and Human Retroviruses. 2016;**32**: 68-79. DOI: 10.1089/aid.2015.0008

[143] Patani R, Balaratnam M, Vora A, Reynolds R. Remyelination can be extensive in multiple sclerosis despite a long disease course. Neuropathology and Applied Neurobiology. 2007;**33**:277-287. DOI: 10.1111/j.1365-2990.2007.00805.x

[144] Williams A, Piaton G, Aigrot MS, Belhadi A, Théaudin M, Petermann F, et al. Semaphorin 3A and 3F: Key players in myelin repair in multiple sclerosis? Brain. 2007;**130**:2554-2565. DOI: 10.1093/brain/awm202

[145] Boyd A, Zhang H, Williams A. Insufficient OPC migration into demyelinated lesions is a cause of poor remyelination in MS and mouse models. Acta Neuropathologica. 2013;**125**:841-859. DOI: 10.1007/ s00401-013-1112-y

[146] Qureshi M, Hatem M, Alroughani R, Jacob SP, Al-Temaimi RA. PLXNA3 variant rs5945430 is associated with severe clinical course in male multiple sclerosis patients. Neuromolecular Medicine. 2017;**19**:286-292. DOI: 10.1007/s12017-017-8443-0

[147] Costa C, Martínez-Sáez E, Gutiérrez-Franco A, Eixarch H, Castro Z, Ortega-Aznar A, et al. Expression of semaphorin 3A, semaphorin 7A and their receptors in multiple sclerosis lesions. Multiple Sclerosis. 2015;**21**:1632-1643. DOI: 10.1177/1352458515599848

[148] Kumanogoh A, Marukawa S, Suzuki K, Takegahara N, Watanabe C, Ch'ng E, et al. Class IV semaphorin Sema4A enhances T-cell activation and interacts with Tim-2. Nature. 2002;**419**:629-633. DOI: 10.1038/ nature01037

[149] Leitner DF, Todorich B, Zhang X, Connor JR. Semaphorin4A is cytotoxic to oligodendrocytes and is elevated in microglia and multiple sclerosis. ASN Neuro. 2015;**7**: 1-13. pii: 1759091415587502. DOI: 10.1177/1759091415587502

[150] Chiou B, Lucassen E, Sather M, Kallianpur A, Connor J. Semaphorin4A and H-ferritin utilize Tim-1 on human oligodendrocytes: A novel neuroimmune axis. Glia. 2018;**66**:1317-1330. DOI: 10.1002/glia.23313

[151] Czopik AK, Bynoe MS, Palm N, Raine CS, Medzhitov R. Semaphorin 7A is a negative regulator of T cell responses. Immunity. 2006;**24**:591-600. DOI: 10.1016/j.immuni.2006.03.013

[152] Koda T, Okuno T, Takata K, Honorat JA, Kinoshita M, Tada S, et al. Sema4A inhibits the therapeutic effect of IFN-β in EAE. Journal of Neuroimmunology. 2014;**268**:43-49. DOI: 10.1016/j.jneuroim.2013.12.014

[153] Okuno T, Nakatsuji Y, Moriya M, Takamatsu H, Nojima S, Takegahara N, et al. Roles of Sema4D-plexin-B1 interactions in the central nervous system for pathogenesis of experimental autoimmune encephalomyelitis. Journal of Immunology. 2010;**184**:1499-1506. DOI: 10.4049/jimmunol.0903302

[154] Comabella M, Fernández M, Martin R, Rivera-Vallvé S, Borrás E, Chiva C, et al. Cerebrospinal fluid chitinase 3-like 1 levels are associated with conversion to multiple sclerosis. Brain. 2010;**133**:1082-1093. DOI: 10.1093/brain/awq035

[155] Cantó E, Tintoré M, Villar LM, Borrás E, Alvarez-Cermeño JC, Chiva C, et al. Validation of semaphorin 7A and ala-β-his-dipeptidase as biomarkers associated with the conversion from clinically isolated syndrome to multiple sclerosis. Journal of Neuroinflammation. 2014;**11**:181. DOI: 10.1186/s12974-014-0181-8

[156] Gutiérrez-Franco A, Costa C, Eixarch H, Castillo M, Medina-Rodríguez EM, Bribián A, et al. Differential expression of sema3A and sema7A in a murine model of multiple sclerosis: Implications for a therapeutic design. Clinical Immunology. 2016;**163**:22-33. DOI: 10.1016/j. clim.2015.12.005

[157] Fisher TL, Reilly CA, Winter LA, Pandina T, Jonason A, Scrivens M, et al. Generation and preclinical characterization of an antibody specific for SEMA4D. mAbs Journal. 2016;**8**:150-162. DOI: 10.1080/19420862.2015.1102813

[158] LaGanke C, Samkoff L, Edwards K, Jung Henson L, Repovic P, Lynch S, et al. Safety/tolerability of the anti-semaphorin 4D antibody VX15/2503 in a randomized phase 1 trial. Neurology: Neuroimmunology & Neuroinflammation. 2017;**4**:e367. DOI: 10.1212/NXI.0000000000000367

**49**

**Chapter 3**

**Abstract**

**1. Introduction**

neurogenesis [1].

**1.2 Anatomy of a neuron**

membranes. It contains a nucleus.

toward the cell body (soma) are known as dendrites.

**1.1 What are neurons?**

Neurodegenerative Diseases and

Alzheimer's disease and Parkinson's disease are characterized as a chronic and progressive neurodegenerative disorder and are manifested by the loss of neurons within the brain and/or spinal cord. In the present chapter, we would like to summarize the molecular mechanism focusing on metabolic modification associated with neurodegenerative diseases or heritable genetic disorders. The identification of the exact molecular mechanisms involved in these diseases would facilitate the discovery of earlier pathophysiological markers along with substantial therapies, which may consist (of) mitochondria-targeted antioxidant therapy, mitochondrial dynamics modulators, epigenetic modulators, and neural stem cell therapy. Therefore, all these therapies may hold particular assurance as influential neuroprotective therapies in the

**Keywords:** neurons, mitochondria-targeted antioxidants, mitochondrial dynamics,

Neurons or nerve cells are the functional unit of the brain and nervous system, and they produce electrical signals known as action potentials. Action potentials permit them to speedily pass on the details over long distances. Their connections define who we are as a person. The creation of new neurons in the brain is known as

Different types of neurons may differ in a number of ways, but they all include three distinct regions with differing functions, that is, the cell body (soma), followed by the dendrites, the axons, and the connected axon terminals (**Figure 1**).

a.Cell body: It is the place of biogenesis of almost all neuronal proteins and

b.Dendrites: The extensions of neurons that receive signals and conduct them

Their Therapeutic Approaches

*Farhin Patel and Palash Mandal*

treatment of neurodegenerative diseases.

epigenetic regulations, stem cell, neurodegenerative diseases

#### **Chapter 3**

*Neurons - Dendrites and Axons*

nature01037

[148] Kumanogoh A, Marukawa S, Suzuki K, Takegahara N, Watanabe C, Ch'ng E, et al. Class IV semaphorin Sema4A enhances T-cell activation and interacts with Tim-2. Nature. 2002;**419**:629-633. DOI: 10.1038/

[155] Cantó E, Tintoré M, Villar LM, Borrás E, Alvarez-Cermeño JC, Chiva C, et al. Validation of semaphorin 7A and ala-β-his-dipeptidase as biomarkers

Neuroinflammation. 2014;**11**:181. DOI:

associated with the conversion from clinically isolated syndrome to multiple sclerosis. Journal of

10.1186/s12974-014-0181-8

[156] Gutiérrez-Franco A, Costa C, Eixarch H, Castillo M, Medina-Rodríguez EM, Bribián A, et al. Differential expression of sema3A and sema7A in a murine model of multiple sclerosis: Implications for a therapeutic

design. Clinical Immunology. 2016;**163**:22-33. DOI: 10.1016/j.

[157] Fisher TL, Reilly CA, Winter LA, Pandina T, Jonason A, Scrivens M, et al. Generation and preclinical characterization of an antibody specific for SEMA4D. mAbs Journal. 2016;**8**:150-162. DOI: 10.1080/19420862.2015.1102813

[158] LaGanke C, Samkoff L, Edwards K, Jung Henson L, Repovic P, Lynch S, et al. Safety/tolerability of the anti-semaphorin 4D antibody VX15/2503 in a randomized phase 1 trial. Neurology: Neuroimmunology & Neuroinflammation. 2017;**4**:e367. DOI: 10.1212/NXI.0000000000000367

clim.2015.12.005

[149] Leitner DF, Todorich B,

10.1177/1759091415587502

DOI: 10.1002/glia.23313

Zhang X, Connor JR. Semaphorin4A is cytotoxic to oligodendrocytes and is elevated in microglia and multiple sclerosis. ASN Neuro. 2015;**7**: 1-13. pii: 1759091415587502. DOI:

[150] Chiou B, Lucassen E, Sather M, Kallianpur A, Connor J. Semaphorin4A and H-ferritin utilize Tim-1 on human oligodendrocytes: A novel neuroimmune axis. Glia. 2018;**66**:1317-1330.

[151] Czopik AK, Bynoe MS, Palm N, Raine CS, Medzhitov R. Semaphorin 7A is a negative regulator of T cell responses. Immunity. 2006;**24**:591-600. DOI: 10.1016/j.immuni.2006.03.013

[152] Koda T, Okuno T, Takata K, Honorat JA, Kinoshita M, Tada S, et al. Sema4A inhibits the therapeutic effect of IFN-β in EAE. Journal of Neuroimmunology. 2014;**268**:43-49. DOI: 10.1016/j.jneuroim.2013.12.014

[153] Okuno T, Nakatsuji Y, Moriya M, Takamatsu H, Nojima S, Takegahara N, et al. Roles of Sema4D-plexin-B1 interactions in the central nervous system for pathogenesis of experimental autoimmune encephalomyelitis. Journal of Immunology. 2010;**184**:1499-1506. DOI: 10.4049/jimmunol.0903302

[154] Comabella M, Fernández M, Martin R, Rivera-Vallvé S, Borrás E, Chiva C, et al. Cerebrospinal fluid chitinase 3-like 1 levels are associated with conversion to multiple sclerosis. Brain. 2010;**133**:1082-1093. DOI:

10.1093/brain/awq035

**48**

## Neurodegenerative Diseases and Their Therapeutic Approaches

*Farhin Patel and Palash Mandal*

#### **Abstract**

Alzheimer's disease and Parkinson's disease are characterized as a chronic and progressive neurodegenerative disorder and are manifested by the loss of neurons within the brain and/or spinal cord. In the present chapter, we would like to summarize the molecular mechanism focusing on metabolic modification associated with neurodegenerative diseases or heritable genetic disorders. The identification of the exact molecular mechanisms involved in these diseases would facilitate the discovery of earlier pathophysiological markers along with substantial therapies, which may consist (of) mitochondria-targeted antioxidant therapy, mitochondrial dynamics modulators, epigenetic modulators, and neural stem cell therapy. Therefore, all these therapies may hold particular assurance as influential neuroprotective therapies in the treatment of neurodegenerative diseases.

**Keywords:** neurons, mitochondria-targeted antioxidants, mitochondrial dynamics, epigenetic regulations, stem cell, neurodegenerative diseases

#### **1. Introduction**

#### **1.1 What are neurons?**

Neurons or nerve cells are the functional unit of the brain and nervous system, and they produce electrical signals known as action potentials. Action potentials permit them to speedily pass on the details over long distances. Their connections define who we are as a person. The creation of new neurons in the brain is known as neurogenesis [1].

#### **1.2 Anatomy of a neuron**

Different types of neurons may differ in a number of ways, but they all include three distinct regions with differing functions, that is, the cell body (soma), followed by the dendrites, the axons, and the connected axon terminals (**Figure 1**).


#### **1.3 Functions of neurons**


#### **1.4 How neurons transmit information throughout the body?**

Neurons converse with other neurons through axons and dendrites. When a neuron receives information from another neuron, it transmits an electrical signal along the length of the respective axon, known as action potential. At the axon terminal, the electrical signal is changed into chemical signal. The axon releases chemical messengers called neurotransmitters. The neurotransmitters are released into the gap between the axon terminal and the tip of a dendrite (receptor site) of a further neuron. The space between the axon terminal and the tip of a dendrite is called a synapse. The neurotransmitters travel along the short distance through the synaptic gap to the dendrite. The dendrite receives the neurotransmitters and translates the chemical signal into electrical signal. This electrical signal travels all the way through the neuron, to be converted back into a chemical signal when it gets to adjoining neurons [4].

**51**

**Figure 2.**

*Factors associated with neurodegenerative diseases*.

*Neurodegenerative Diseases and Their Therapeutic Approaches*

Etymologically, the word neurodegeneration comprises of "neuro," which refers to neurons, and "degeneration," which refers to the process of losing structure and/ or function of either tissues or organs [5]. A neurodegenerative disease is considered as a slow, progressive failure of nerve cells within the central nervous system (CNS). This leads to deficits in particular brain functions like learning, movement,

and cognition generally performed by the CNS (brain and spinal cord).

b.Oxidative stress and reactive oxygen species (ROS) formation

c.Impaired bioenergetics and mitochondrial dysfunction

d.Excessive exposure to metals and pesticides (**Figure 2**)

**2.2 Classification based on molecular defects**

syndrome, and fetal familial insomnia [8].

a.Aberrant protein dynamics with aggregation and degradation of defective

a.Trinucleotide repeat diseases: HD, spinal cerebellar atrophy, and myotonic

b.Prion diseases: Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker

**2.1 Factors associated with neurodegenerative diseases**

*DOI: http://dx.doi.org/10.5772/intechopen.82129*

**2. Neurodegenerative diseases**

protein [6]

dystrophy [7].

**Figure 1.** *Anatomy of neuron.*

### **2. Neurodegenerative diseases**

*Neurons - Dendrites and Axons*

cell [2].

**1.3 Functions of neurons**

c.Synaptic transmission [3]

gets to adjoining neurons [4].

a.Conduction and transmission of nerve impulses

**1.4 How neurons transmit information throughout the body?**

Neurons converse with other neurons through axons and dendrites. When a neuron receives information from another neuron, it transmits an electrical signal along the length of the respective axon, known as action potential. At the axon terminal, the electrical signal is changed into chemical signal. The axon releases chemical messengers called neurotransmitters. The neurotransmitters are released into the gap between the axon terminal and the tip of a dendrite (receptor site) of a further neuron. The space between the axon terminal and the tip of a dendrite is called a synapse. The neurotransmitters travel along the short distance through the synaptic gap to the dendrite. The dendrite receives the neurotransmitters and translates the chemical signal into electrical signal. This electrical signal travels all the way through the neuron, to be converted back into a chemical signal when it

b.Initiation and conduction of action potential

c.Axon (nerve fiber): The extensions of neurons that conduct the signals away from the cell body to the other nerve cells or neuron are known as axons.

d.Axon terminal (end-plate): The end part or terminal part of axons that makes a synaptic contact with other nerve cells is known as an axon terminal. It is responsible for the initiation of transmission of nerve impulse to another nerve

**50**

**Figure 1.** *Anatomy of neuron.*

Etymologically, the word neurodegeneration comprises of "neuro," which refers to neurons, and "degeneration," which refers to the process of losing structure and/ or function of either tissues or organs [5]. A neurodegenerative disease is considered as a slow, progressive failure of nerve cells within the central nervous system (CNS). This leads to deficits in particular brain functions like learning, movement, and cognition generally performed by the CNS (brain and spinal cord).

#### **2.1 Factors associated with neurodegenerative diseases**


#### **2.2 Classification based on molecular defects**


**Figure 2.** *Factors associated with neurodegenerative diseases*.


### **3. Alzheimer's disease**

Alzheimer's disease (AD) is an irreparable, progressive neurodegenerative disease that affects normal brain functioning [11]. It is mainly the general cause of dementia [12]. Dementia is a syndrome associated with memory loss and loss of abilities like thinking, reasoning, and language skills along with other mental illness [12].

#### **3.1 History**

This disease is named after Dr. Alois Alzheimer. He observed some brain tissue abnormalities in an old woman who died due to some unusual mental illness. Later, he examined her brain and found many abnormal tangled bundles of fibers (called as tau tangles, neurofibrillary) and clumps (called as amyloid plaques). That is how he found the cause of AD [13].

#### **3.2 Causes**

The cause of AD is not clearly understood.

	- 1.Autosomal dominant inheritance: Also known as early-onset familial AD [15], it occurs due to the mutation in one of the three genes: Presenilin 1, presenilin 2, or amyloid precursor protein (APP) [16].

Aβ42: A protein that is the main component of senile plaques, and the levels are increased due to mutation in APP and presenilin genes [17].

2.Sporadic Alzheimer's disease: In this type of AD, genetic and environmental factors play a major role.

Example: Inheritance of the epsilon 4 allele of the apolipoprotein E (APOE) [18, 19].


#### **3.3 Molecular mechanism**

(a) Proteopathy: AD has been recognized by plaque formation occurring due to abnormal folding of amyloid beta (Aβ) protein and tau protein in the nerve cells

**53**

apoptosis [30] (**Figure 3**).

*Molecular mechanism of AD.*

**Figure 3.**

transport system [31].

toxicity in rats [34].

**3.4 Therapeutic approaches**

*3.4.1 Mitochondrial-directed therapies*

*Neurodegenerative Diseases and Their Therapeutic Approaches*

(brain) leading to the degeneration of nerve cells [24]. The amyloid precursor protein (APP) leads to the formation of Aβ. APP plays an important role in neuronlike developments and post-injury repair mechanism and survival [25, 26]. In AD, secreting enzymes like β-secretase and γ-secretase together will break down APP into small fragments that penetrate through the neuron membrane [27]. This leads to the formation of Aβ fibrils that later cluster together to form senile plaques and deposits in the outer side of neurons [28, 29]. Aggregated amyloid fibrils accumulation leads to the disruption of cell's calcium ion homeostasis, which results in

(b) Tauopathy: In AD, there is an abnormal accumulation of tau protein. Upon phosphorylation, tau protein stabilizes the microtubules, and it is known as microtubule-associated protein. Tau protein undergoes certain chemical changes, and becomes hyperphosphorylated. This leads to the formation of neurofibrillary tangles upon aggregation with other threads, which results in decaying the neuro-

Decline of N-acetyl aspartate and creatine is associated with dementia [32]. Supplementation of creatine was found to protect neurons in AD [33]. In hippocampal neurons, administration of creatine defends against glutamate and Aβ

In AD patients, administration of lipoic acid (600 mg/day) [LA - an antioxidant; coenzyme for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase]

*DOI: http://dx.doi.org/10.5772/intechopen.82129*

*Neurodegenerative Diseases and Their Therapeutic Approaches DOI: http://dx.doi.org/10.5772/intechopen.82129*

*Neurons - Dendrites and Axons*

dementia [9].

**3. Alzheimer's disease**

he found the cause of AD [13].

of many specific genes [14].

factors play a major role.

**3.3 Molecular mechanism**

The cause of AD is not clearly understood.

**3.1 History**

**3.2 Causes**

c.Synucleinopathies: PD, progressive supranuclear palsy and diffuse Lewy body

d.Tauopathies: Corticobasal degeneration, frontotemporal dementia with parkin-

Alzheimer's disease (AD) is an irreparable, progressive neurodegenerative disease that affects normal brain functioning [11]. It is mainly the general cause of dementia [12]. Dementia is a syndrome associated with memory loss and loss of abilities like thinking, reasoning, and language skills along with other mental illness [12].

This disease is named after Dr. Alois Alzheimer. He observed some brain tissue abnormalities in an old woman who died due to some unusual mental illness. Later, he examined her brain and found many abnormal tangled bundles of fibers (called as tau tangles, neurofibrillary) and clumps (called as amyloid plaques). That is how

a.Genetic: Nearly, 70% of the cases are related to genetic factors with the involvement

1.Autosomal dominant inheritance: Also known as early-onset familial AD [15], it occurs due to the mutation in one of the three genes: Presenilin 1,

Aβ42: A protein that is the main component of senile plaques, and the levels are

2.Sporadic Alzheimer's disease: In this type of AD, genetic and environmental

Example: Inheritance of the epsilon 4 allele of the apolipoprotein E (APOE) [18, 19].

b.Cholinergic hypothesis: The cholinergic hypothesis states that AD is caused

c.Amyloid hypothesis: The amyloid hypothesis states that AD is caused by the

d.Tau hypothesis: The tau hypothesis states that AD is caused due to abnormalities in tau protein, leading to the disintegration of microtubules in nerve cells [22, 23].

(a) Proteopathy: AD has been recognized by plaque formation occurring due to abnormal folding of amyloid beta (Aβ) protein and tau protein in the nerve cells

presenilin 2, or amyloid precursor protein (APP) [16].

increased due to mutation in APP and presenilin genes [17].

by the reduced synthesis of neurotransmitter acetylcholine [20].

deposits of extracellular amyloid beta (Aβ) [21].

sonism linked to chromosome 1\(FTDP-17), and pick disease [10].

**52**

**Figure 3.** *Molecular mechanism of AD.*

(brain) leading to the degeneration of nerve cells [24]. The amyloid precursor protein (APP) leads to the formation of Aβ. APP plays an important role in neuronlike developments and post-injury repair mechanism and survival [25, 26]. In AD, secreting enzymes like β-secretase and γ-secretase together will break down APP into small fragments that penetrate through the neuron membrane [27]. This leads to the formation of Aβ fibrils that later cluster together to form senile plaques and deposits in the outer side of neurons [28, 29]. Aggregated amyloid fibrils accumulation leads to the disruption of cell's calcium ion homeostasis, which results in apoptosis [30] (**Figure 3**).

(b) Tauopathy: In AD, there is an abnormal accumulation of tau protein. Upon phosphorylation, tau protein stabilizes the microtubules, and it is known as microtubule-associated protein. Tau protein undergoes certain chemical changes, and becomes hyperphosphorylated. This leads to the formation of neurofibrillary tangles upon aggregation with other threads, which results in decaying the neurotransport system [31].

#### **3.4 Therapeutic approaches**

#### *3.4.1 Mitochondrial-directed therapies*

Decline of N-acetyl aspartate and creatine is associated with dementia [32]. Supplementation of creatine was found to protect neurons in AD [33]. In hippocampal neurons, administration of creatine defends against glutamate and Aβ toxicity in rats [34].

In AD patients, administration of lipoic acid (600 mg/day) [LA - an antioxidant; coenzyme for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase] stabilizes the cognitive measures [35, 36]. Decreased oxidative stress of mitochondria in fibroblasts was found in AD patients due to LA and/or N-acetyl cysteine (antioxidant and glutathione precursor) administration [37].

CoQ10 (an antioxidant and cofactor of the electron transport chain) blocks apoptosis by inhibiting the permeability transition pore (PTP) of mitochondria [38]. Treatment of CoQ10 neutralizes the brain mitochondrial alterations made by amyloid-β1–40 [39]. CoQ10 was shown to protect paraquat and rotenone-induced mitochondrial dysfunction and neuronal death in SHSY-5Y cells (human neuroblastoma cells) and primary rat mesencephalic neurons, [40, 41]. In R6/2 mice, combined treatment of CoQ10 and minocycline reduces HTT accumulation, brain atrophy, and striatal neuron atrophy [42].

MitoQ (mitochondrial coenzyme Q ) reduces oxidative stress and prevents mitochondrial dysfunction [43]. Oral administration of MitoQ (1 mg/kg body weight) showed better pharmacokinetics behavior with plasma (Cmax = 33.15 ng/ml and Tmax = 1 hr.) in Phase I trial (Antipodean Pharmaceuticals Inc., San Francisco, CA).

#### *3.4.2 Stem cell therapy*

Neural stem cell therapy provides a potential to neurons derived from stem cells to integrate with existing neuronal network of the host brain [44]. In animal models, stem cell transplantation elevates the level of acetylcholine, resulting in an improved cognitive and memory function. Stem cells secrete neurotrophic factors, which modulate neuroplasticity and neurogenesis [45, 46].

Embryonic stem cells (ESCs)-derived neuron progenitor cells (NPCs) when transplanted into an amyloid-β injured in vitro model, after 2 weeks of amyloid-β injection, showed an increased escape latency when compared with phosphatebuffered saline-treated controls [47]. It has been reported that ESCs-derived NPCs improve memory impairment in AD models [48].

Human induced pluripotent stem cell (iPSC) therapy delivers a possible strategy for drug development against AD [49]. Neurons differentiated from iPSCs increase the secretion of amyloid-β42 as it is affected by γ-secretase inhibitors [50].

Bone marrow (BM)-derived mesenchymal stem cells (MSCs) play an important role in the removal of amyloid-β plaques from the hippocampus [51]. Human MSCs promoted amyloid-β clearance and enhanced autophagy and neuronal survival in an amyloid-β-treated mouse model [46]. Transplantation of adipose-derived MSCs (AMSCs) into AD brain improved the acetylcholine levels along with microglia activation and cognitive functions [52, 53]. In a transgenic mouse model, human umbilical cord-derived MSCs differentiated themselves into neuron-like cells, and these cells when transplanted into an amyloid-β precursor protein (AβPP) and PS1 (AβPP/PS1) resulted in improved cognitive function and decreased amyloid β deposition [54].

#### *3.4.3 Epigenetic modulators*

Histone deacetylases have been linked to AD. Treatment with HDACi (histone deacetylase inhibitors) induced dendrite growth, increased the number of synapses, and restored learning and memory deficits in mice with AD [55] (**Table 1**).

#### *3.4.4 Mitochondrial dynamics modulators*

Two recent studies have also shown the protective effects mediated by inhibition of mitochondrial fission via Drp1 deficiency on mitochondria and neurons in tau and APP transgenic animal models for AD [60, 61].

**55**

**Table 2.**

*Genes involved in PD.*

*Neurodegenerative Diseases and Their Therapeutic Approaches*

memory.

shortage.

memory

*Histone deacetylase inhibitors and their respective functions in AD.*

Parkinson's disease (PD) is a progressive, long-term neurodegenerative disorder that affects the motor neurons [62]. It is caused by a loss of neurons in the brain part known as substantia nigra leading to a reduction in a neurotransmitter called

In in vivo and in vitro studies, SIRT1 reduces the

amyloidogenic processing of APP

**HDACi Function References**

protein and programmed cell death resulting in restoring

InTg2576 mouse model, 4-PBA restores fear learning and rescues dendritic spine losses that are associated with memory

In mutant mice model, systemic treatment restores contextual

[56]

[57]

[58]

[59]

Sodium butyrate In neuroblastoma cells, it induces phosphorylation of tau

In 1817, James Parkinson (before known as Jean-Martin Charcot) published an essay named "Shaking Palsy" describing six cases of paralysis agitans showing

(a) Environmental factors: Exposure to metals, solvents, and pesticides, or any

(b) Genetics: Few percent of cases are developing this disease due to mutation in

The mechanism involved in the development of PD includes various factors like the aggregations of misfolded proteins, activation of protein degradation

Autosomal-dominant PD PARK1/PARK4 SNCA (α-synuclein) [68, 69, 72]

Autosomal-recessive PD PARK6 PINK1 [68, 70–72]

**Name Gene References**

PARK2 Parkin [68, 69, 72] PARK5 UCHL [68, 69, 72] PARK8 LRRK2 [68, 69, 72]

PARK7 DJ-1 [68, 70–72]

In 1865, William Sanders termed this disease as Parkinson's disease [65].

head injuries are considered to be a factor for the onset of PD [66, 67].

one specific gene out of several genes related to PD (**Table 2**).

*DOI: http://dx.doi.org/10.5772/intechopen.82129*

**4. Parkinson's disease**

Phenylbutyrate (4-PBA)

Suberoylanilide hydroxamic acid

Resveratrol (activator of class III

HDAC)

**Table 1.**

certain characteristics of this disease [63, 64].

The following are the causes of PD:

**4.3 Molecular mechanism**

dopamine [62].

**4.1 History**

**4.2 Causes**


**Table 1.**

*Neurons - Dendrites and Axons*

CA).

*3.4.2 Stem cell therapy*

stabilizes the cognitive measures [35, 36]. Decreased oxidative stress of mitochondria in fibroblasts was found in AD patients due to LA and/or N-acetyl cysteine

CoQ10 (an antioxidant and cofactor of the electron transport chain) blocks apoptosis by inhibiting the permeability transition pore (PTP) of mitochondria [38]. Treatment of CoQ10 neutralizes the brain mitochondrial alterations made by amyloid-β1–40 [39]. CoQ10 was shown to protect paraquat and rotenone-induced mitochondrial dysfunction and neuronal death in SHSY-5Y cells (human neuroblastoma cells) and primary rat mesencephalic neurons, [40, 41]. In R6/2 mice, combined treatment of CoQ10 and minocycline reduces HTT accumulation, brain

MitoQ (mitochondrial coenzyme Q ) reduces oxidative stress and prevents mitochondrial dysfunction [43]. Oral administration of MitoQ (1 mg/kg body weight) showed better pharmacokinetics behavior with plasma (Cmax = 33.15 ng/ml and Tmax = 1 hr.) in Phase I trial (Antipodean Pharmaceuticals Inc., San Francisco,

Neural stem cell therapy provides a potential to neurons derived from stem cells to integrate with existing neuronal network of the host brain [44]. In animal models, stem cell transplantation elevates the level of acetylcholine, resulting in an improved cognitive and memory function. Stem cells secrete neurotrophic factors,

Embryonic stem cells (ESCs)-derived neuron progenitor cells (NPCs) when transplanted into an amyloid-β injured in vitro model, after 2 weeks of amyloid-β injection, showed an increased escape latency when compared with phosphatebuffered saline-treated controls [47]. It has been reported that ESCs-derived NPCs

Human induced pluripotent stem cell (iPSC) therapy delivers a possible strategy for drug development against AD [49]. Neurons differentiated from iPSCs increase

Bone marrow (BM)-derived mesenchymal stem cells (MSCs) play an important role in the removal of amyloid-β plaques from the hippocampus [51]. Human MSCs promoted amyloid-β clearance and enhanced autophagy and neuronal survival in an amyloid-β-treated mouse model [46]. Transplantation of adipose-derived MSCs (AMSCs) into AD brain improved the acetylcholine levels along with microglia activation and cognitive functions [52, 53]. In a transgenic mouse model, human umbilical cord-derived MSCs differentiated themselves into neuron-like cells, and these cells when transplanted into an amyloid-β precursor protein (AβPP) and PS1 (AβPP/PS1) resulted in improved cognitive function and decreased amyloid β

Histone deacetylases have been linked to AD. Treatment with HDACi (histone deacetylase inhibitors) induced dendrite growth, increased the number of synapses, and restored learning and memory deficits in mice with AD [55] (**Table 1**).

Two recent studies have also shown the protective effects mediated by inhibition of mitochondrial fission via Drp1 deficiency on mitochondria and neurons in tau

the secretion of amyloid-β42 as it is affected by γ-secretase inhibitors [50].

(antioxidant and glutathione precursor) administration [37].

which modulate neuroplasticity and neurogenesis [45, 46].

improve memory impairment in AD models [48].

atrophy, and striatal neuron atrophy [42].

**54**

deposition [54].

*3.4.3 Epigenetic modulators*

*3.4.4 Mitochondrial dynamics modulators*

and APP transgenic animal models for AD [60, 61].

*Histone deacetylase inhibitors and their respective functions in AD.*

### **4. Parkinson's disease**

Parkinson's disease (PD) is a progressive, long-term neurodegenerative disorder that affects the motor neurons [62]. It is caused by a loss of neurons in the brain part known as substantia nigra leading to a reduction in a neurotransmitter called dopamine [62].

#### **4.1 History**

In 1817, James Parkinson (before known as Jean-Martin Charcot) published an essay named "Shaking Palsy" describing six cases of paralysis agitans showing certain characteristics of this disease [63, 64].

In 1865, William Sanders termed this disease as Parkinson's disease [65].

#### **4.2 Causes**

The following are the causes of PD:

(a) Environmental factors: Exposure to metals, solvents, and pesticides, or any head injuries are considered to be a factor for the onset of PD [66, 67].

(b) Genetics: Few percent of cases are developing this disease due to mutation in one specific gene out of several genes related to PD (**Table 2**).

#### **4.3 Molecular mechanism**

The mechanism involved in the development of PD includes various factors like the aggregations of misfolded proteins, activation of protein degradation


pathways, mitochondrial damage, and oxidative stress, along with certain gene mutations [73–75].

#### *4.3.1 Aggregation of misfolded proteins*



#### *4.3.2 Protein degradation pathways*




#### *4.3.3 Damage to mitochondria and oxidative stress*


#### *4.3.4 Genetic mutations*

The most common genes related to PD are α-synuclein, DJ-1, PINK1, and Parkin [88] (**Table 3**).

#### **4.4 Therapeutic approaches**

#### *4.4.1 Mitochondria-directed therapies*

Administration of creatine increases tyrosine hydroxylase immunoreactive fiber density and soma size of dopaminergic neurons in mesencephalic cultures by protecting against neurotoxic insults induced by serum and glucose deprivation, MPP+, and 6-hydroxydopamine [33, 92]. It has been reported that dopamine loss was prevented by administration of creatine. In substantia nigra, creatine also

**57**

dropyridine (MPTP) [93].

*4.4.2 Stem cell therapy*

protection on dopaminergic neurons in PD [96].

fibrils [95].

PINK1 (PARK6)

**Table 3.**

**Figure 4.**

*Molecular mechanism of PD.*

*Neurodegenerative Diseases and Their Therapeutic Approaches*

reduces loss of neuron in the mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahy-

DJ-1 (PARK7) Activities like transcriptional regulation, antioxidants, chaperone, and

protease are dysregulated

Mitochondrial dysfunctioning Degeneration of substantia nigra neuron

*Specific gene mutations and their dysfunction involved in the development of PD.*

CoQ10 protects against iron-induced apoptosis in dopaminergic neurons [94]. In vitro, CoQ10 exerts anti-amyloidogenic effects by disrupting preformed amyloid-β

**Genes Dysfunction References** α-synuclein Aggregation of misfolded amyloid proteins [89] Parkin Aggregation of misfolded amyloid proteins within SNpc [89]

[90]

[91]

SS peptides (Szeto Schiller) act as antioxidants that target mitochondria in an independent manner. In mice, reports showed that SS-20 and SS-31 provide protection against MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) neurotoxicity. SS-31 provides protection against dopamine loss in the striatum. In substantia nigra, SS-31 also provides protection against the loss of tyrosine hydroxylase

immunoreactive neurons. In MPTP-treated mice, SS-20 provides potential neuronal

In the first trial of cell-based therapy, post-mitotic dopamine neuroblasts isolated from human embryonic mesencephalic tissue have been successfully grafted in PD patients [97]. It has been confirmed through increase in 18F-dopa intake,

*DOI: http://dx.doi.org/10.5772/intechopen.82129*

*Neurodegenerative Diseases and Their Therapeutic Approaches DOI: http://dx.doi.org/10.5772/intechopen.82129*



#### **Table 3.**

*Neurons - Dendrites and Axons*

*4.3.1 Aggregation of misfolded proteins*

*4.3.2 Protein degradation pathways*

the degradation of misfolded α-synuclein [79]

*4.3.3 Damage to mitochondria and oxidative stress*

mutations [73–75].

pars compacta [75]

tau protein [81, 82]

*4.3.4 Genetic mutations*

**4.4 Therapeutic approaches**

*4.4.1 Mitochondria-directed therapies*

[88] (**Table 3**).

tangles [76]

pathways, mitochondrial damage, and oxidative stress, along with certain gene







The most common genes related to PD are α-synuclein, DJ-1, PINK1, and Parkin

Administration of creatine increases tyrosine hydroxylase immunoreactive fiber density and soma size of dopaminergic neurons in mesencephalic cultures by protecting against neurotoxic insults induced by serum and glucose deprivation, MPP+, and 6-hydroxydopamine [33, 92]. It has been reported that dopamine loss was prevented by administration of creatine. In substantia nigra, creatine also

**56**

*Specific gene mutations and their dysfunction involved in the development of PD.*

reduces loss of neuron in the mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [93].

CoQ10 protects against iron-induced apoptosis in dopaminergic neurons [94]. In vitro, CoQ10 exerts anti-amyloidogenic effects by disrupting preformed amyloid-β fibrils [95].

SS peptides (Szeto Schiller) act as antioxidants that target mitochondria in an independent manner. In mice, reports showed that SS-20 and SS-31 provide protection against MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) neurotoxicity. SS-31 provides protection against dopamine loss in the striatum. In substantia nigra, SS-31 also provides protection against the loss of tyrosine hydroxylase immunoreactive neurons. In MPTP-treated mice, SS-20 provides potential neuronal protection on dopaminergic neurons in PD [96].

#### *4.4.2 Stem cell therapy*

In the first trial of cell-based therapy, post-mitotic dopamine neuroblasts isolated from human embryonic mesencephalic tissue have been successfully grafted in PD patients [97]. It has been confirmed through increase in 18F-dopa intake,

#### *Neurons - Dendrites and Axons*

detected through positron emission tomography (PET) [98, 99]. The grafts restore dopamine release. Disadvantages of this therapy are limited tissue availability and grafts standardization.

Recently, researchers have shed light on stem cell therapy. The production of dopamine neuroblasts from stem cells for transplantation in PD patients has been focused on. The aim was to release dopamine in a stable manner and exhibit the electrophysiological, molecular, and morphological properties of substantia nigra neurons [100, 101]. In clinical trials, it has been found that dopaminergic cells derived from embryonic stem cells can survive and reverse behavioral deficits after transplantation in PD animal models [102, 103].

#### *4.4.3 Epigenetic modulators*

In sporadic PD patients, there is an increased α-synuclein expression in dopaminergic neurons, which is linked with α-synuclein hypomethylation [104]. In familial PD patients, decreased histone acetylation is linked with increased α-synuclein levels [105]. In vitro model, mutation in α-synuclein leads to increased histone acetylation mediated through HDAC Sirt2. Treatment of Sirt2 siRNA resulted in decreased α-synuclein-mediated toxicity [106]. Administration of levodopa elevated the dopamine level, which partially showed decreased symptoms of PD. It is correlated with deacetylation of H4K5, K12, and K16 [107].

#### *4.4.4 Mitochondrial dynamics modulators*

Recombinant adeno-associated virus expressing the dominant negative Drp1 (dynamin-related protein 1) mutant or Mdivi-1, a small molecular inhibitor of Drp1, has been reported to inhibit mitochondrial fragmentation, restore dopamine release, and prevent dopamine neuron loss in PD animal models [108].

Activation of DRP1-mediated mitochondrial fission is an important contributing factor in the progression of PD. Neurons lacking PINK or Parkin accumulate DRP1, resulting in excessive mitochondrial fission, increased oxidative stress, and reduced ATP production [108, 109]. These defects can be reversed by the inhibition of mitochondrial fission with the use of mdivi-1, an inhibitor of the DRP1 pathway, or by overexpression of MFN2 (Mitofusin 2) or OPA1 (Optic atrophy protein 1) [109, 110].

In vitro models of glutamate-toxicity or OGD (oxygen-glucose deprivation) in mouse hippocampal neurons or in vivo mouse models of transient focal ischemia can be protected from enhanced mitochondrial fission and apoptosis by DRP1 knockdown or mdivi-1 inhibition [111, 112].

#### **5. Conclusion**

The recent advancements in the field of neurodegenerative diseases like AD and PD are based on targeting the degenerative progressions that lead to the death of neurons. The death of neurons leads to irreversible neuropathological conditions, making it difficult to be functional in humans. Because of the intricacy involved in respective neurodegenerative diseases, researchers have identified few potential biomarkers. At present, many therapeutic approaches have been suggested to treat the symptoms of both neurodegenerative diseases. Yet there exists a lacuna for the effective therapies. Hence, few therapeutic approaches like mitochondria-targeted antioxidant therapy, mitochondrial dynamics modulators, epigenetic modulators, and neural stem cell therapy may prove to have a potential in treating AD and PD.

**59**

**Author details**

Farhin Patel and Palash Mandal\*

Science and Technology, Gujarat, India

provided the original work is properly cited.

*Neurodegenerative Diseases and Their Therapeutic Approaches*

Authors have no conflict of interest to declare.

*DOI: http://dx.doi.org/10.5772/intechopen.82129*

**Conflict of interest**

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Biological Sciences, P.D.Patel Institute of Applied Sciences, Charotar University of

\*Address all correspondence to: palashmandal.bio@charusat.ac.in

*Neurodegenerative Diseases and Their Therapeutic Approaches DOI: http://dx.doi.org/10.5772/intechopen.82129*

### **Conflict of interest**

*Neurons - Dendrites and Axons*

grafts standardization.

*4.4.3 Epigenetic modulators*

transplantation in PD animal models [102, 103].

*4.4.4 Mitochondrial dynamics modulators*

knockdown or mdivi-1 inhibition [111, 112].

detected through positron emission tomography (PET) [98, 99]. The grafts restore dopamine release. Disadvantages of this therapy are limited tissue availability and

Recently, researchers have shed light on stem cell therapy. The production of dopamine neuroblasts from stem cells for transplantation in PD patients has been focused on. The aim was to release dopamine in a stable manner and exhibit the electrophysiological, molecular, and morphological properties of substantia nigra neurons [100, 101]. In clinical trials, it has been found that dopaminergic cells derived from embryonic stem cells can survive and reverse behavioral deficits after

In sporadic PD patients, there is an increased α-synuclein expression in dopaminergic neurons, which is linked with α-synuclein hypomethylation [104]. In familial PD patients, decreased histone acetylation is linked with increased α-synuclein levels [105]. In vitro model, mutation in α-synuclein leads to increased histone acetylation mediated through HDAC Sirt2. Treatment of Sirt2 siRNA resulted in decreased α-synuclein-mediated toxicity [106]. Administration of levodopa elevated the

Recombinant adeno-associated virus expressing the dominant negative Drp1 (dynamin-related protein 1) mutant or Mdivi-1, a small molecular inhibitor of Drp1, has been reported to inhibit mitochondrial fragmentation, restore dopamine

Activation of DRP1-mediated mitochondrial fission is an important contributing factor in the progression of PD. Neurons lacking PINK or Parkin accumulate DRP1, resulting in excessive mitochondrial fission, increased oxidative stress, and reduced ATP production [108, 109]. These defects can be reversed by the inhibition of mitochondrial fission with the use of mdivi-1, an inhibitor of the DRP1 pathway, or by overexpression of MFN2 (Mitofusin 2) or OPA1 (Optic atrophy protein 1)

In vitro models of glutamate-toxicity or OGD (oxygen-glucose deprivation) in mouse hippocampal neurons or in vivo mouse models of transient focal ischemia can be protected from enhanced mitochondrial fission and apoptosis by DRP1

The recent advancements in the field of neurodegenerative diseases like AD and PD are based on targeting the degenerative progressions that lead to the death of neurons. The death of neurons leads to irreversible neuropathological conditions, making it difficult to be functional in humans. Because of the intricacy involved in respective neurodegenerative diseases, researchers have identified few potential biomarkers. At present, many therapeutic approaches have been suggested to treat the symptoms of both neurodegenerative diseases. Yet there exists a lacuna for the effective therapies. Hence, few therapeutic approaches like mitochondria-targeted antioxidant therapy, mitochondrial dynamics modulators, epigenetic modulators, and neural stem cell therapy may prove to have a potential in treating AD and PD.

dopamine level, which partially showed decreased symptoms of PD. It is correlated with deacetylation of H4K5, K12, and K16 [107].

release, and prevent dopamine neuron loss in PD animal models [108].

**58**

[109, 110].

**5. Conclusion**

Authors have no conflict of interest to declare.

### **Author details**

Farhin Patel and Palash Mandal\* Biological Sciences, P.D.Patel Institute of Applied Sciences, Charotar University of Science and Technology, Gujarat, India

\*Address all correspondence to: palashmandal.bio@charusat.ac.in

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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*Neurons - Dendrites and Axons*

ISBN 978-971-23-4807-5

[3] Dudel J. Function of nerve cells. In: Schmidt RF, Thews G, editors. Human Physiology. Berlin, Heidelberg: Springer; 1983. DOI: 10.1007/978-3-642-96714-6\_1

[1] Chudler EH. Brain Facts and Figures. Neuroscience for Kids. Retrieved:

Biochemical Society Symposium.

[11] Burns A, Iliffe S. Alzheimer's disease. BMJ. 2009;**338**:b158. DOI:

[12] Dementia Fact sheet. World Health Organization. December 12, 2017

[13] Scott KR, Barrett AM. Dementia

[14] Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer's disease. Lancet. 2011;**377**(9770):1019-1031. DOI: 10.1016/S0140-6736(10)61349-9

[15] Blennow K, de Leon MJ, Zetterberg

2006;**368**(9533):387-403. DOI: 10.1016/

[17] Selkoe DJ. Translating cell biology into therapeutic advances in Alzheimer's

disease. Nature. 1999;**399**(6738 Suppl):A23-A31. DOI: 10.1038/19866

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hmg/ddp012

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ldn013

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**67**

*Neurodegenerative Diseases and Their Therapeutic Approaches*

*DOI: http://dx.doi.org/10.5772/intechopen.82129*

Striatal histone modifications in models of levodopa-induced dyskinesia. Journal of Neurochemistry. 2008;**106**:486-494

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[110] Grünewald A, Gegg ME, Taanman J-W, et al. Differential effects of PINK1 nonsense and missense mutations on mitochondrial function and

morphology. Experimental Neurology.

[111] Zhang N, Wang S, Li Y, et al. A selective inhibitor of Drp1, mdivi-1, acts against cerebral ischemia/

reperfusion injury via an anti-apoptotic pathway in rats. Neuroscience Letters.

[112] Zhao Y-X, Cui M, Chen S-F, et al. Amelioration of ischemic mitochondrial

membrane permeabilization by Mdivi-1. CNS Neuroscience & Therapeutics.

injury and Bax-dependent outer

2009;**284**:13843-13855

2009;**219**:266-273

2013;**535**:104-109

2014;**20**:528-538

*Neurodegenerative Diseases and Their Therapeutic Approaches DOI: http://dx.doi.org/10.5772/intechopen.82129*

Striatal histone modifications in models of levodopa-induced dyskinesia. Journal of Neurochemistry. 2008;**106**:486-494

*Neurons - Dendrites and Axons*

[PubMed: 15890457]

[PubMed: 10222117]

[PubMed: 16679553]

the survival of dopaminergic neurons in cultured fetal ventral mesencephalic tissue. Neuroscience. 2005;**133**:701-713. [100] Mendez I et al. Cell type analysis of functional fetal dopamine cell suspension transplants in the striatum and substantia nigra of patients with Parkinson's disease. Brain.

[101] Isacson O et al. Toward full restoration of synaptic and terminal function of the dopaminergic system in Parkinson's disease by stem cells. Annals of Neurology. 2003;**53**(Suppl.

[102] Winkler C et al. Transplantation in the rat model of Parkinson's disease: Ectopic versus homotopic graft

placement. Progress in Brain Research.

Transplantation. NewYork: Raven Press;

[104] Jowaed A, Schmitt I, Kaut O, Wullner U. Methylation regulates alphasynuclein expression and is decreased in Parkinson's disease patients' brains. The Journal of Neuroscience.

[103] Brundin P et al. Functional effects of mesencephalic and adrenal chromoffin cells grafted in the rodent striatum. In: Dunnett SB, Björklund A, editors. Functional Neural

2005;**128**:1498-1510

3):S135-S146

2000;**127**:233-265

1994. pp. 9-46

2010;**30**:6355-6359

[105] Voutsinas GE, Stavrou EF, Karousos G, Dasoula A,

Mutation. 2010;**31**:685-691

Science. 2007;**317**:516-519

[106] Outeiro TF, Kontopoulos E,

Altmann SM, Kufareva I, Strathearn KE, Amore AM, et al. Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease.

[107] Nicholas AP, Lubin FD, Hallett PJ, Vattem P, Ravenscroft P, Bezard E, et al.

Papachatzopoulou A, Syrrou M, et al. Allelic imbalance of expression and epigenetic regulation within the alphasynuclein wild-type and p.Ala53Thr alleles in Parkinson disease. Human

[93] Matthews RT, Ferrante RJ, Klivenyi P, Yang L, Klein AM, Mueller G, et al. Creatine and cyclocreatine attenuate MPTP neurotoxicity. Experimental Neurology. 1999;**157**:142-149.

[94] Kooncumchoo P, Sharma S, Porter J, Govitrapong P, Ebadi M. Coenzyme Q(10) provides neuroprotection in iron-induced apoptosis in dopaminergic

neurons. Journal of Molecular Neuroscience. 2006;**28**:125-141.

[95] Ono K, Hasegawa K, Naiki H, Yamada M. Preformed betaamyloid fibrils are destabilized by coenzyme Q10 in vitro. Biochemical

Communications. 2005;**330**:111-116.

[96] Yang L, Zhao K, Calingasan NY, Luo G, Szeto HH, Beal F. Mitochondria targeted peptides protect against 1-methyl-4-phenyl-1, 2, 3,

6-tetrahydropyridine neurotoxicity. Antioxidants & Redox Signaling.

[97] Lindvall O, Kokaia Z. Prospects of stem cell therapy for replacing dopamine neurons in Parkinson's disease. Trends in Pharmacological Sciences.2009;**30**(5):260-267

[98] Brundin P et al. Bilateral caudate and putamen grafts of embryonic mesencephalic tissue treated with lazaroids in Parkinson's disease. Brain.

[99] Wenning GK et al. Short- and long-term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson's disease. Annals of

Neurology. 1997;**42**:95-107

and Biophysical Research

[PubMed: 15781239]

2009;**11**(9):2095-2104

2000;**123**:1380-1390

**66**

[108] Rappold PM, Cui M, Grima JC, Fan RZ, de Mesy-Bentley KL, Chen L, et al. Drp1 inhibition attenuates neurotoxicity and dopamine release deficits in vivo. Nature Communications. 2014;**5**:5244

[109] Dagda RK, Cherra SJ, Kulich SM, et al. Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. The Journal of Biological Chemistry. 2009;**284**:13843-13855

[110] Grünewald A, Gegg ME, Taanman J-W, et al. Differential effects of PINK1 nonsense and missense mutations on mitochondrial function and morphology. Experimental Neurology. 2009;**219**:266-273

[111] Zhang N, Wang S, Li Y, et al. A selective inhibitor of Drp1, mdivi-1, acts against cerebral ischemia/ reperfusion injury via an anti-apoptotic pathway in rats. Neuroscience Letters. 2013;**535**:104-109

[112] Zhao Y-X, Cui M, Chen S-F, et al. Amelioration of ischemic mitochondrial injury and Bax-dependent outer membrane permeabilization by Mdivi-1. CNS Neuroscience & Therapeutics. 2014;**20**:528-538

**69**

Section 3

Gap Junction
