**1. Introduction**

Alzheimer's disease (AD) is a neurodegenerative disease affecting 5.4 million people globally and is predicated to affect over 100 million people worldwide by 2050 [1]. It is the most common form of progressive cognitive decline. As originally described by Alois Alzheimer in 1907, AD is associated with extracellular amyloid plaque formation and intracellular neurofibrillary tangles in the brain regions involved in learning and memory processes [2]. A major problem of the disease is, perhaps, altered proteolytic processing of the amyloid precursor protein (APP) resulting in the production and aggregation of neurotoxic forms of Aβ. Amyloid plaques are extracellular deposits of fibrils and amorphous aggregates of β-amyloid (Aβ). Compact plaques have been considered to be associated with neuronal and synaptic loss, dystrophic neurites, hypertrophic astrocytes, activated microglia cells, and various features of inflamma‐ tory processes. The intracellular neurofibrillary tangles consist of paired helical filaments formed by the microtubule-associated protein tau that exhibits hyperphosphorylation and oxidative modifications. Increasing lines of evidence have shown that visual impairment is associated with the prevalence of AD [3]-[5].

Glaucoma is recognized as an age-related neurodegenerative disorder – optic neuropathy. Being the second leading cause of blindness, it is estimated that glaucoma will affect more than 80 million people worldwide with at least 6 - 8 million individuals becoming bilaterally blind by the year 2020 [6]. Comparing to normal population, the prevalence of glaucoma is about 2.5 times higher in AD patients [7]. In 2011, Nucci and co-workers reported that glaucoma progression was associated with altered levels of Aβ and tau proteins in cerebral spinal fluid

© 2013 Chiu et al.; licensee InTech. This is an open access article 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. © 2013 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.

[8]. The intravitreous levels of Aβ1-42 are significantly decreased and that of tau are markedly increased in glaucoma patients [9]. We propose that accumulation of Aβ and hyperphos‐ phorylated tau protein should be considered to be new pathological factors to propagate neurodegeneration in glaucoma.

ment of tau from microtubules leads to dysfunction of axonal transport and even retraction of spines[25]. Apart from stabilizing microtubules, tau has a more versatile role in the central nervous system (CNS). Tau regulates the process of neurite extension via its ability to stop microtubule-severing proteins and its facilitative role on nerve growth factor signaling [26]. Tau interacts via its amino-terminal projection domain with the kinase Fyn (a proto-oncogene tyrosine-protein kinase). Fyn phosphorylates the N-methyl-D-aspartate receptor (NMDAR) to link NMDAR to synaptic excitotoxic downstream signaling [27]. Recent findings also reported that Tau can modulate phospholipase C gamma [28], histone deacetylase-6 [29], and heat shock proteins [30]. Tau also interacts with actin via acidic N-terminals, projecting from microtubules for neurite outgrowth and stabilization during the brain development [31]. In tau knockout

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In the retina, tau not only regulates the cytoskeleton and axonal transport in retinal neurons, but also affects accumulation of Aβ and cell survival signaling. The pivotal roles of tau in retinal

It has been found that tau is expressed in a gradient manner in retinal ganglion cells (RGC), with higher levels in the terminal parts of axons of developing RGCs. Its localization at the axon plays a role in proper axon development and survival of RGCs [33]. Exposure to okadaic acid resulted in accumulation of phosphorylated tau, followed by distortion of the cytoskeleton leading to growth cone collapse. Hence, tau has been implicated in the process of establishing neuronal axon polarity [34]. Interruption in these transport mechanisms would cause the accumulation of Aβ, which can propagate secondary degeneration. Studies based on Tg2576 transgenic mice showed that immunoreactivity of hyperphosphorylated tau was found to be

Tau can be phosphorylated by cyclin-dependent kinase 5 (Cdk5), a proline-directed serine/ threonine kinase. Phosphorylation leads tau to dissociate from microtubules and affects its stability. Cdk5 is highly expressed in neuronal axons and growth cones serving to promote neurite outgrowth and migration[36]. To initiate its activation, Cdk5 requires interaction with its activator subunit p35. Cdk5 has been implicated to phosphorylate various substrates to regulate a diverse range of cellular processes in the CNS. Studies have shown that ephrin-A signaling pathway can also lead to the activation of Cdk5. Ephrin-A regulates retinotectal projection via receptor-mediated axon growth repulsion through a complex signaling cascade. Fyn can activate Cdk5 to phosphorylate collapsin response mediator protein (CRMP2) to reduce microtubule assembly[37]. Immunofluorescence studies have shown that activation of Cdk5 occurs downstream of ephrin-A5 signaling to phosphorylate tau in the growth cones and axons of RGCs. These findings suggest that phosphorylation of tau serves as another means to which ephrin-A signaling can induce microtubule reorganization in RGC growth

Apart from Cdk5, tau has also been found to interact with calcium/calmodulin-dependent protein kinase II (CaMKII) in the CaMKII-α-associated protein complex in chick retina. Endogenous association of tau with CaMKII-α suggests that it is important in regulating

mice, neurogenesis is severely reduced [32].

*1.2.2. Multiple functions of tau in the retina*

functions are summarized in Figure 1.

very close to that of Aβ in mouse retina [35].

cones[38].

#### **1.1. Amyloid precursor protein and functions**

APP is a type I transmembrane protein with a single transmembrane domain, a large extrac‐ ellular ectodomain, and a short cytoplasmic tail [10]. The processing of APP to Aβ is an important event in the pathogenesis of AD [11]. The processing is initiated by cleavage of APP by α-secretase within the Aβ region, and by cleavage by β-secretase (BACE) at the amino terminus of Aβ, leading to the secretion of large soluble ectodomains. In pathological situation, if the carboxyl-terminal fragments is processed by γ-secretase resulting in the production of Aβ, p3, and the APP intracellular domain (AICD). In humans, the *APP* gene is located on chromosome 21 with three major isoforms (APP695, APP751 and APP770) arising from alternative splicing [12]. APP is highly expressed in neurons where the protein is rapidly transported down the axons to nerve terminus in the brain and retina [13].

As the processing of APP to Aβ is an important event in the pathogenesis of AD, great effort has been devoted to understand biological functions of APP since its cloning in 1988 [10]. In vitro and in vivo studies have shown important activities of APP in modulating neurite outgrowth [14], synaptic activity [15]-[17], metal homeostasis [18], [19], synaptic transmission [20] and synaptic adhesion at the neuromuscular junction [21]. In retina, APP plays a role in retinogenesis. In APP knockout (KO) mice, differentiation of some inner retinal neurons, specifically horizontal and amacrine cells are hampered in APP-KO mice during early postnatal development[22]. However, normal numbers of horizontal cells and most types of amacrine cells are found in adult APP-KO mice. The number is similar to adult C57/B6JxSV129 wild type control mice. APP is expressed in inner retina including horizontal, cone bipolar, amacrine and ganglion cells in the APP-KO mice. Although APP is not required for gross retinal structure or visual acuity in adult retina, it is required for the inner retinal function of the rod and cone pathway [23].

#### **1.2. Tau protein and functions**

#### *1.2.1. Tau protein*

Tau protein is microtubule-associated protein that stabilizes microtubules and able to form aggregation in pathological conditions. Tau is expressed from the gene known as microtubuleassociated protein tau (MAPT) on chromosome 17 at position 17q21. Tau is highly expressed in neurons and is abundant in axons [24]. Hyperphosphorylated, insoluble, and filamentous tau proteins were shown to be the main component of neurofibrillary tangles (NFTs), a pathological hallmark of AD [24].

Tau binding to microtubules enables them to play a fundamental role in promoting microtu‐ bule assembly and stability; and in turn, affecting intra-neuronal transport of cargos. Detach‐ ment of tau from microtubules leads to dysfunction of axonal transport and even retraction of spines[25]. Apart from stabilizing microtubules, tau has a more versatile role in the central nervous system (CNS). Tau regulates the process of neurite extension via its ability to stop microtubule-severing proteins and its facilitative role on nerve growth factor signaling [26]. Tau interacts via its amino-terminal projection domain with the kinase Fyn (a proto-oncogene tyrosine-protein kinase). Fyn phosphorylates the N-methyl-D-aspartate receptor (NMDAR) to link NMDAR to synaptic excitotoxic downstream signaling [27]. Recent findings also reported that Tau can modulate phospholipase C gamma [28], histone deacetylase-6 [29], and heat shock proteins [30]. Tau also interacts with actin via acidic N-terminals, projecting from microtubules for neurite outgrowth and stabilization during the brain development [31]. In tau knockout mice, neurogenesis is severely reduced [32].

#### *1.2.2. Multiple functions of tau in the retina*

[8]. The intravitreous levels of Aβ1-42 are significantly decreased and that of tau are markedly increased in glaucoma patients [9]. We propose that accumulation of Aβ and hyperphos‐ phorylated tau protein should be considered to be new pathological factors to propagate

APP is a type I transmembrane protein with a single transmembrane domain, a large extrac‐ ellular ectodomain, and a short cytoplasmic tail [10]. The processing of APP to Aβ is an important event in the pathogenesis of AD [11]. The processing is initiated by cleavage of APP by α-secretase within the Aβ region, and by cleavage by β-secretase (BACE) at the amino terminus of Aβ, leading to the secretion of large soluble ectodomains. In pathological situation, if the carboxyl-terminal fragments is processed by γ-secretase resulting in the production of Aβ, p3, and the APP intracellular domain (AICD). In humans, the *APP* gene is located on chromosome 21 with three major isoforms (APP695, APP751 and APP770) arising from alternative splicing [12]. APP is highly expressed in neurons where the protein is rapidly

As the processing of APP to Aβ is an important event in the pathogenesis of AD, great effort has been devoted to understand biological functions of APP since its cloning in 1988 [10]. In vitro and in vivo studies have shown important activities of APP in modulating neurite outgrowth [14], synaptic activity [15]-[17], metal homeostasis [18], [19], synaptic transmission [20] and synaptic adhesion at the neuromuscular junction [21]. In retina, APP plays a role in retinogenesis. In APP knockout (KO) mice, differentiation of some inner retinal neurons, specifically horizontal and amacrine cells are hampered in APP-KO mice during early postnatal development[22]. However, normal numbers of horizontal cells and most types of amacrine cells are found in adult APP-KO mice. The number is similar to adult C57/B6JxSV129 wild type control mice. APP is expressed in inner retina including horizontal, cone bipolar, amacrine and ganglion cells in the APP-KO mice. Although APP is not required for gross retinal structure or visual acuity in adult retina, it is required for the inner retinal function of

Tau protein is microtubule-associated protein that stabilizes microtubules and able to form aggregation in pathological conditions. Tau is expressed from the gene known as microtubuleassociated protein tau (MAPT) on chromosome 17 at position 17q21. Tau is highly expressed in neurons and is abundant in axons [24]. Hyperphosphorylated, insoluble, and filamentous tau proteins were shown to be the main component of neurofibrillary tangles (NFTs), a

Tau binding to microtubules enables them to play a fundamental role in promoting microtu‐ bule assembly and stability; and in turn, affecting intra-neuronal transport of cargos. Detach‐

transported down the axons to nerve terminus in the brain and retina [13].

neurodegeneration in glaucoma.

158 Glaucoma - Basic and Clinical Aspects

the rod and cone pathway [23].

**1.2. Tau protein and functions**

pathological hallmark of AD [24].

*1.2.1. Tau protein*

**1.1. Amyloid precursor protein and functions**

In the retina, tau not only regulates the cytoskeleton and axonal transport in retinal neurons, but also affects accumulation of Aβ and cell survival signaling. The pivotal roles of tau in retinal functions are summarized in Figure 1.

It has been found that tau is expressed in a gradient manner in retinal ganglion cells (RGC), with higher levels in the terminal parts of axons of developing RGCs. Its localization at the axon plays a role in proper axon development and survival of RGCs [33]. Exposure to okadaic acid resulted in accumulation of phosphorylated tau, followed by distortion of the cytoskeleton leading to growth cone collapse. Hence, tau has been implicated in the process of establishing neuronal axon polarity [34]. Interruption in these transport mechanisms would cause the accumulation of Aβ, which can propagate secondary degeneration. Studies based on Tg2576 transgenic mice showed that immunoreactivity of hyperphosphorylated tau was found to be very close to that of Aβ in mouse retina [35].

Tau can be phosphorylated by cyclin-dependent kinase 5 (Cdk5), a proline-directed serine/ threonine kinase. Phosphorylation leads tau to dissociate from microtubules and affects its stability. Cdk5 is highly expressed in neuronal axons and growth cones serving to promote neurite outgrowth and migration[36]. To initiate its activation, Cdk5 requires interaction with its activator subunit p35. Cdk5 has been implicated to phosphorylate various substrates to regulate a diverse range of cellular processes in the CNS. Studies have shown that ephrin-A signaling pathway can also lead to the activation of Cdk5. Ephrin-A regulates retinotectal projection via receptor-mediated axon growth repulsion through a complex signaling cascade. Fyn can activate Cdk5 to phosphorylate collapsin response mediator protein (CRMP2) to reduce microtubule assembly[37]. Immunofluorescence studies have shown that activation of Cdk5 occurs downstream of ephrin-A5 signaling to phosphorylate tau in the growth cones and axons of RGCs. These findings suggest that phosphorylation of tau serves as another means to which ephrin-A signaling can induce microtubule reorganization in RGC growth cones[38].

Apart from Cdk5, tau has also been found to interact with calcium/calmodulin-dependent protein kinase II (CaMKII) in the CaMKII-α-associated protein complex in chick retina. Endogenous association of tau with CaMKII-α suggests that it is important in regulating

and finding objects [44]-[46], depth perception [43] perceiving structure from motion [44], [46]- [48], color recognition [44], [49], and impairment in spatial contrast sensitivity [47], [50]. Previously, these changes have been attributed to neuronal damage to the visual pathways in the brain rather than the retina [51]. However, there are increasing lines of evidence showing that specific AD like pathology (amyloid plaques and NFT) in the brain can be found in the retina. In 2011, Koronyn-Hamaoui and co-workers [52] identified amyloid plaques in the

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Cross-sectional imaging of the retina using optical coherence tomography (OCT) has demon‐ strated a significant reduction of thickness in peripapillary retinal fiber layer (RFL) of patients with early AD when compared with age-matched controls[53]-[57]. The thinning of RFL was observed predominantly in the inferior and superior quadrants, which was consistent with the inferior and superior visual field loss in AD patients[44], [54]. Reduction of the macular thickness has also been reported in AD; and the total volume of the macula is inversely correlated with the severity of the disease[55]. Changes in the optic nerve head have been observed using confocal scanning laser ophthalmoscopy (cSLO). The observed changes include reduced RFL thickness, neuroretinal rim volume and area, and increased cup-disc ratio; suggesting an overall reduction in the number of optic nerve fibers passing through the optic nerve head [58]. These *in vivo* findings are corroborated by the histopathological findings of axonal degeneration in optic nerves, reduced thickness of RFL and a significant reduction

retinas from AD patients as well as patients in mild cognitive impairment.

in the number of large diameter RGCs in the post-mortem AD retinas [59], [60].

eration of RGCs in glaucoma.

**3. Retinal degeneration in AD transgenic mice**

According to the definitions of glaucoma published in 2002 by an international consensus panel [61], glaucoma is thought to be present when at least one eye has typical defects both in structural and functional aspects (optic disc damage and visual field loss, respectively) [62]. Characteristically, the damage indicates the death of RGC in the inner retina and loss of axons in the optic nerve. This structural loss of the axons can be recognized clinically by ophthal‐ moscope or can be detected by imaging devices such as OCT and scanning laser polarimetry. Besides NFL thinning, the similarities between the ocular effects of AD and glaucoma can be observed in pattern electroretinogram (PERG) responses [63], [64], the type of cell loss (large magnocellular RGC) and possibly the mechanisms for loss of RGC (apoptosis) [65], [66]. This may explain the high incidence of glaucoma in AD patients [7], [67]. The involvement of Aβ accumulation and hyperphosphorylated tau protein might be important causes of neurodegn‐

Since there is a lack of postmortem human retinal samples from AD patients, progress of investigating pathogenesis of retinal neurodegeneration in the AD eyes is slow. Much of the insights have gained from specific gene mutations that account for the familial AD (FAD). The majority (30-40%) of FAD is resulted from autosomal dominant inheritance with mutated genes encoding presenilin 1 (PS1) on the long arm of chromosome 14, presenilin 2 (PS2) on chromosome 1 and amyloid precursor protein (APP) on chromosome 21 [68].

**Figure 1.** Schematic diagram summarizing the roles of tau in retinal functions. Tau stabilizes microtubules. Dislocation of Tau from microtubules can result in growth cone collapse. Accumulation of β-amyloid (Aβ) is an example to trigger phosphorylation of tau and hence detaches from microtubule. Apart from Aβ as a triggering factor, any stimulation of signaling cascade of cdk5, ephrin-A receptor or calmodulin-dependent protein kinase II affecting phosphorylation of tau can also modulate microtubules. Once tau leaves microtubules after phosphorylation, they can easily form aggre‐ gation, which can further impair axonal transport mediated by kinesin or dynein. Consequently, mitochondria in the distal part of nerve, nerve terminus or spines cannot obtain protection from the cell body (soma) so that they are col‐ lapse and cannot produce energy. Neurodegeneration can unavoidably occur.

cytoskeletal assembly in neurons. Through the phosphorylation of tau, microtubule assembly may be inhibited; and hence, the cellular architecture is disrupted[39].

**Figure 2. Chiu et al., 2012**

Abnormally aggregated tau inhibits the transportation of mitochondria by kinesin-like motors towards the cell periphery of rat RGCs. Consequently, neurons with perturbation of mito‐ chondria and peroxisomes suffer from loss of energy production and accumulation of reactive oxygen species (ROS). The anterograde transport of vesicles required for growth cones and synaptic function is retarded. In addition, these neurons may be more vulnerable to oxidative stress[40]. In the RGCs axons of P301S mutant mice, the projection domain of tau interacts with the C-terminus of p150, the major component of the dynein-activator. The co-localization of tau and p150 suggests that tau dysfunction can result in the mislocalization of dynactin in axons, which can result in neurodegeneration[41].
