Preface

Chapter 7 **High Temporal Resolution Brain Microdialysis as a Tool to**

**Section 3 Growth, Development and Differentiation 223**

Chapter 8 **Participation of Neurochemical Signaling in Adult Neurogenesis and Differentiation 225** E.V. Pushchina, A.A. Varaksin and D.K. Obukhov

**Trophic Activity 257**

**Section 4 Neurodegenerative Diseases 283**

Chapter 10 **Alzheimer Disease: The Role of Aβ in the Glutamatergic System 285**

Chapter 11 **Genetics of Alzheimer´S Disease 317**

Meraz-Ríos

Ríos

Chapter 9 **Physiological Role of Amyloid Beta in Neural Cells: The Cellular**

Victoria Campos-Peña and Marco Antonio Meraz-Ríos

Chapter 12 **Accumulation of Abnormally Processed Tau Protein in**

Aguayo, R. Mena and M.A. Meraz Ríos

Chapter 13 **Energy-Dependent Mechanisms of Cholinergic**

**Neurodegeneration 375**

Szutowicz

**Neuronal Cells as a Biomarker for Dementia 355**

Victoria Campos-Peña, Rocío Gómez and Marco Antonio Meraz

J. Luna-Muñoz, A. Martínez-Maldonado, V. Ibarra-Bracamontes, M. A. Ontiveros-Torres, I. Ferrer, B. Floran-Garduño, M. del C. Cárdenas-

Agnieszka Jankowska-Kulawy, Anna Ronowska and Andrzej

M. del C. Cárdenas-Aguayo, M. del C. Silva-Lucero, M. Cortes-Ortiz, B. Jiménez-Ramos, L. Gómez-Virgilio, G. Ramírez-Rodríguez, E. Vera-Arroyo, R. Fiorentino-Pérez, U. García, J. Luna-Muñoz and M.A.

Parrot

**VI** Contents

**Investigate the Dynamics of Interactions Between Olfactory Cortex and Amygdala in Odor Fear Conditioning 199** Chloé Hegoburu, Luc Denoroy, Anne-Marie Mouly and Sandrine

> Neurochemistry is a flourishing academic field that contributes to our understanding of mo‐ lecular, cellular and medical neurobiology. As a scientific discipline, neurochemistry studies the role of chemicals that build the nervous system, explores the function of neurons and glial cells in health and disease, discovers aspects of cell metabolism and neurotransmission, and reveals how degenerative processes are at work in the nervous system. Accordingly, this book contains chapters from a variety of topics that fall into the following broad sec‐ tions: I. Neural Membranes and Intracellular Signaling, II. Neural Processing and Intercellu‐ lar Signaling, III. Growth, Development and Differentiation, and IV. Neurodegenerative Diseases. The book presents comprehensive reviews in these different areas written by ex‐ perts in their respective fields. Neurodegeneration and neuronal diseases are featured prom‐ inently and are a recurring theme throughout most chapters. This book will be a most valuable resource for neurochemists and other scientists alike. In addition, it will contribute to the training of current and future neurochemists and, hopefully, will lead us on the path to curing some of the biggest challenges in human health.

> Section One of the book, I. Neural Membranes and Intracellular Signaling, starts with a dis‐ cussion of the blood brain barrier by Dalvi et al. (chapter 1: 'The Blood Brain Barrier: Regula‐ tion of Fatty acid and Drug Transport') to introduce the reader to chemicals that enter the brain. The chapter has a strong focus on tight junctions. Dalvi et al. describe the various tight junction proteins and transport systems and provide a solid account of the role of fatty acids in blood brain barrier permeability.

> In chapter 2 ('TRP Channels in Neuronal and Glial Signal Transduction'), Harteneck and Leuner provide a comprehensive review of transient receptor potential (TRP) channels and their relation to various neurological and psychiatric diseases. Many TRP channels are ex‐ pressed in the brain and contribute to neuronal and glial functions. The authors offer de‐ tailed accounts of the many channel variants and their functional roles in CNS physiology.

> In chapter 3 ('Cytosolic Calcium Homeostasis in Neurons: Control Systems, Modulation by Reactive Oxygen and Nitrogen Species, and Space and Time Fluctuations'), Gutierrez-Meri‐ no et al. review the critical role of calcium in neuronal activity and function of the nervous systems. The authors discuss cellular oxidative stress and metabolic deregulations in the process of neuronal death. Calcium transport systems control cytosolic calcium homeostasis within nanodomains of the neuronal plasma membrane associated with lipid rafts. The colocalization of ROS/RNS enzyme sources within nanodomains is of particular relevance for neurodegenerative insults and diseases.

> In chapter 4, Section Two, II. Neural Processing and Intercellular Signaling, Tsetlin and Ka‐ sheverov ('Peptide and Protein Neurotoxin Toolbox in Research on Nicotinic Acetylcholine

Receptors') examine nicotinic acetylcholine receptors and the neurotoxins that helped re‐ searchers to identify their structure and function. The chapter takes the reader on a historical journey of the discovery of the receptor and its various peptide and protein neurotoxins.

In chapter 12 ('Accumulation of Abnormally Processed Tau Protein in Neuronal Cells as a Biomarker for Dementia'), Luna-Muñoz et al. inform the reader about the problem of early detection and better treatment of neurodegenerative disorders such as Alzheimer's and Par‐ kinson's disease. They discuss the development of better therapeutic tools that are able to modify the disease progression based on reliable biomarkers to detect the disease at early

In the final chapter of the book (ch. 13, 'Energy–Dependent Mechanisms of Cholinergic Neu‐ rodegeneration'), Jankowska-Kulawy et al. point out that a characteristic feature of some neurodegenerative diseases is the preferential loss of cholinergic neurons which correlate with the degree of energy metabolism inhibition. Even though neurons constitute only 10% of all brain cells, they produce and consume about 80% of its energy. The authors raise the critical issue that effective functioning of neurons is dependent on the continuous supply of glucose and oxygen. The authors discuss energy homeostasis of the brain as a complex proc‐ ess because of the high sensitivity of neurons to metabolic stress, the isolation of the brain due to the existence of the blood brain barrier, the high energy requirements of the brain, and the existence of limited glycogen stores as a dynamic source of energy. Despite these constraints, dysfunction of mitochondria, the cellular source of energy, is the first step in

I am grateful to InTech – Open Access Publisher for initiating this book project and for ask‐ ing me to serve as its editor. Many thanks go to Iva Lipović at InTech for guiding me through the publication process and for moving the book ahead in a timely fashion. Thanks are due to all contributors of this book for taking the time to first write a chapter proposal, compose their chapter and, lastly, make my requested revisions to it. Hopefully, all contrib‐ utors will continue their neurochemistry research with many intellectual challenges and ex‐ citing new directions. I would like to thank my wife Dr. Vonnie D.C. Shields, Professor, Towson University, Towson, MD and our son Torben Heinbockel for allowing me to spend time on this book project during the past year. Finally, I am grateful to my parents Erich and

**Thomas Heinbockel, Ph.D.**

Department of Anatomy

Preface IX

Washington, DC, USA

Associate Professor and Director of Graduate Studies

Howard University College of Medicine

stages to prevent the irreversible neuronal degeneration.

Renate Heinbockel for their support over many years.

neurodegeneration.

In chapter 5 ('Synaptic Soluble and Membrane-Bound Choline Acetyltransferase as a Marker of Cholinergic Function in Vitro and in Vivo'), Zakharova and Dudchenko address the syn‐ apse as a unique, most dynamic and labile structure and discuss the use of synaptosomes to study neural transmission, specifically at cholinergic synapses. The authors explore the brain cholinergic system because of its role in cognitive, attention and motor functions as well as dysfunctions related to several neurological disorders.

Chapter 6 by Heinbockel ('Neurochemical Communication: The Case of Endocannabinoids') reviews the progress made in our understanding of a relatively novel neuronal signaling system, the endocannabinoid system which comprises endogenously produced cannabi‐ noids and their specific receptors, cannabinoid receptors. This signaling system plays a criti‐ cal role in neuronal communication in many brain areas and has been shown to crosstalk with other neurotransmitter system.

In chapter 7 ('High Temporal Resolution Brain Microdialysis as a Tool to Investigate the Dy‐ namics of Interactions Between Olfactory Cortex and Amygdala in Odor Fear Condition‐ ing'), Hegoboru et al. report how a specific experimental tool, in vivo microdialysis of major amino acid neurotransmitters, allows studying the interaction of two brain areas in a behav‐ ioral context.

Section Three, III. Growth, Development and Differentiation, houses two chapters. Chapter 8 by Pushchina et al. ('Participation of Neurochemical Signaling in Adult Neurogenesis and Differentiation') explores the organization and relationships of signal transduction systems that produce classic neurotransmitters or gaseous transmitters in the brain of fish and evalu‐ ates their participation in the processes of the postembryonic morphogenesis the CNS.

For quite some time, amyloid plaques in the body have been accepted as a cause of the neu‐ rodegeneration observed in Alzheimer's disease based on the hypothesis that the amyloid beta peptide is a toxic factor that impairs neuronal function and leads to cell death, see Sec‐ tion IV. In chapter 9 ('Physiological Role of Amyloid Beta in Neural Cells: The Cellular Tro‐ phic Activity'), Cárdenas-Aguayo et al. challenge this hypothesis by reviewing the physiological roles of amyloid beta and suggest that amyloid beta might even help to en‐ hance synaptic plasticity and memory at appropriate concentration levels.

The last section, Section IV, is dedicated to Neurodegenerative Diseases. In chapter 10 ('Alz‐ heimer Disease: the Role of Aβ in the Glutamatergic System'), Campos-Peña and Meraz-Ríos review the neurodegenerative process that occurs in Alzheimer's disease. The authors discuss the role of the glutamatergic system and the use of safe disease-modifying drugs in the treatment of Alzheimer's disease.

In chapter 11, the authors (Campos-Peña, Gómez, Meraz-Ríos) continue with a discussion of the 'Genetics of Alzheimer's Disease'. They review the evidence for a genetic basis of fami‐ lial Alzheimer's disease, also known as early onset Alzheimer's disease which is associated with mutations in different genes. In contrast, sporadic Alzheimer's disease or late onset Alzheimer's disease is much more common and the cause for it might be a combination of lifestyle, environmental and some genetic factors which could favor the development of the disease.

In chapter 12 ('Accumulation of Abnormally Processed Tau Protein in Neuronal Cells as a Biomarker for Dementia'), Luna-Muñoz et al. inform the reader about the problem of early detection and better treatment of neurodegenerative disorders such as Alzheimer's and Par‐ kinson's disease. They discuss the development of better therapeutic tools that are able to modify the disease progression based on reliable biomarkers to detect the disease at early stages to prevent the irreversible neuronal degeneration.

Receptors') examine nicotinic acetylcholine receptors and the neurotoxins that helped re‐ searchers to identify their structure and function. The chapter takes the reader on a historical journey of the discovery of the receptor and its various peptide and protein neurotoxins. In chapter 5 ('Synaptic Soluble and Membrane-Bound Choline Acetyltransferase as a Marker of Cholinergic Function in Vitro and in Vivo'), Zakharova and Dudchenko address the syn‐ apse as a unique, most dynamic and labile structure and discuss the use of synaptosomes to study neural transmission, specifically at cholinergic synapses. The authors explore the brain cholinergic system because of its role in cognitive, attention and motor functions as

Chapter 6 by Heinbockel ('Neurochemical Communication: The Case of Endocannabinoids') reviews the progress made in our understanding of a relatively novel neuronal signaling system, the endocannabinoid system which comprises endogenously produced cannabi‐ noids and their specific receptors, cannabinoid receptors. This signaling system plays a criti‐ cal role in neuronal communication in many brain areas and has been shown to crosstalk

In chapter 7 ('High Temporal Resolution Brain Microdialysis as a Tool to Investigate the Dy‐ namics of Interactions Between Olfactory Cortex and Amygdala in Odor Fear Condition‐ ing'), Hegoboru et al. report how a specific experimental tool, in vivo microdialysis of major amino acid neurotransmitters, allows studying the interaction of two brain areas in a behav‐

Section Three, III. Growth, Development and Differentiation, houses two chapters. Chapter 8 by Pushchina et al. ('Participation of Neurochemical Signaling in Adult Neurogenesis and Differentiation') explores the organization and relationships of signal transduction systems that produce classic neurotransmitters or gaseous transmitters in the brain of fish and evalu‐ ates their participation in the processes of the postembryonic morphogenesis the CNS.

For quite some time, amyloid plaques in the body have been accepted as a cause of the neu‐ rodegeneration observed in Alzheimer's disease based on the hypothesis that the amyloid beta peptide is a toxic factor that impairs neuronal function and leads to cell death, see Sec‐ tion IV. In chapter 9 ('Physiological Role of Amyloid Beta in Neural Cells: The Cellular Tro‐ phic Activity'), Cárdenas-Aguayo et al. challenge this hypothesis by reviewing the physiological roles of amyloid beta and suggest that amyloid beta might even help to en‐

The last section, Section IV, is dedicated to Neurodegenerative Diseases. In chapter 10 ('Alz‐ heimer Disease: the Role of Aβ in the Glutamatergic System'), Campos-Peña and Meraz-Ríos review the neurodegenerative process that occurs in Alzheimer's disease. The authors discuss the role of the glutamatergic system and the use of safe disease-modifying drugs in

In chapter 11, the authors (Campos-Peña, Gómez, Meraz-Ríos) continue with a discussion of the 'Genetics of Alzheimer's Disease'. They review the evidence for a genetic basis of fami‐ lial Alzheimer's disease, also known as early onset Alzheimer's disease which is associated with mutations in different genes. In contrast, sporadic Alzheimer's disease or late onset Alzheimer's disease is much more common and the cause for it might be a combination of lifestyle, environmental and some genetic factors which could favor the development of the

hance synaptic plasticity and memory at appropriate concentration levels.

well as dysfunctions related to several neurological disorders.

with other neurotransmitter system.

the treatment of Alzheimer's disease.

ioral context.

VIII Preface

disease.

In the final chapter of the book (ch. 13, 'Energy–Dependent Mechanisms of Cholinergic Neu‐ rodegeneration'), Jankowska-Kulawy et al. point out that a characteristic feature of some neurodegenerative diseases is the preferential loss of cholinergic neurons which correlate with the degree of energy metabolism inhibition. Even though neurons constitute only 10% of all brain cells, they produce and consume about 80% of its energy. The authors raise the critical issue that effective functioning of neurons is dependent on the continuous supply of glucose and oxygen. The authors discuss energy homeostasis of the brain as a complex proc‐ ess because of the high sensitivity of neurons to metabolic stress, the isolation of the brain due to the existence of the blood brain barrier, the high energy requirements of the brain, and the existence of limited glycogen stores as a dynamic source of energy. Despite these constraints, dysfunction of mitochondria, the cellular source of energy, is the first step in neurodegeneration.

I am grateful to InTech – Open Access Publisher for initiating this book project and for ask‐ ing me to serve as its editor. Many thanks go to Iva Lipović at InTech for guiding me through the publication process and for moving the book ahead in a timely fashion. Thanks are due to all contributors of this book for taking the time to first write a chapter proposal, compose their chapter and, lastly, make my requested revisions to it. Hopefully, all contrib‐ utors will continue their neurochemistry research with many intellectual challenges and ex‐ citing new directions. I would like to thank my wife Dr. Vonnie D.C. Shields, Professor, Towson University, Towson, MD and our son Torben Heinbockel for allowing me to spend time on this book project during the past year. Finally, I am grateful to my parents Erich and Renate Heinbockel for their support over many years.

#### **Thomas Heinbockel, Ph.D.**

Associate Professor and Director of Graduate Studies Department of Anatomy Howard University College of Medicine Washington, DC, USA

**Section 1**

**Neural Membranes and Intracellular Signaling**

**Neural Membranes and Intracellular Signaling**

**Chapter 1**

**The Blood Brain Barrier — Regulation of Fatty Acid and**

The blood brain barrier (BBB) is a selectively permeable cellular boundary between the brain and the peripheral circulation. The principal component of the BBB is the capillary or micro‐ vessel endothelial cell (Figure 1). The endothelial cells in the brain capillaries differ from those

**1.** Presence of tight junctions (TJ) that limit the paracellular passage of macromolecules.

**2.** Restricted rate of fluid-phase endocytosis that limits the transcellular passage of macro‐

Thus, the endothelial cells of the BBB are less "leaky" than those of the peripheral vessels. However, it has been shown that if the endothelial cells of the brain capillaries are removed from their natural environment and allowed to vascularize the peripheral tissue, they become more leaky [1]. In contrast, the endothelial cells from the periphery form tight junctions when allowed to vascularize the brain parenchyma. Morphologically, the tight junctions of the BBB

> © 2014 The Author(s). Licensee InTech. 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.

**Drug Transport**

Grant M. Hatch

**1. Introduction**

http://dx.doi.org/10.5772/57604

**1.1. The blood brain barrier**

molecules [1]

**4.** Lack of fenestrations [3]

**5.** Increased mitochondrial content [3]

Siddhartha Dalvi, Ngoc On, Hieu Nguyen, Michael Pogorzelec, Donald W. Miller and

Additional information is available at the end of the chapter

in the peripheral vasculature in several key features:

**3.** Presence of specific transporter and carrier molecules [2]
