**5. TAU and glaucoma**

In double transgenic mice strain APPswe/PS1M146L, Aβ was found to deposit predominantly in NFL and RGCL in aged mice of 27 months but not at young mice of 7.8 months. In another double transgenic strain APPswe/PS1∆E9, similar Aβ deposition was detected in intermediate age of 10.5 months[11]. In another subsequent study using transgenic mice APPswe/PS1∆E9, Aβ plaques were found by thioflavin-S staining in plexiform layers; the size and the number of plaques significantly increased with age from 12 months[77]. The transparent nature of the eyes allows direct tracking and visualization of the Aβ signal has also been detected in the retinal and choroidal vasculature. In single transgenic Tg2576 mice, Aβ was detected around microvessels in RGCL[73], [76]. Both retinal and choroidal vascular Aβ deposits were reported in aged (27 months) APPswe/PS1M146L transgenic mice and intermediate-aged (10.5 months)

Hyperphosphorylation of tau protein and subsequent deposition as neurofilbrillary tangles is associated with AD. Tau inclusions have been observed in the brains as well as in the retinas of Tg2576 and triple transgenic mice [79]. In single transgenic Tg2576 mice, hyperphosphory‐ lated tau was detected by antibody AT8 in various retinal layers from RGCL through to the ONL. The hyperphosphorylated tau was found to be associated with Aβ depositions [73]. Another single transgenic expresses human P301S tau transgene, hyperphosphorylated tau was found to deposit in the RNFL and aggregated into filamentous inclusions in RGCs starting from 2-month-old mice [78]. Hyperphosphorylation and aggregation of tau were associated *in vivo* with reduced axonal transport, both anterograde and retrograde, in the optic nerve of

Glial reactions, activated microglia and astrocytes, in the retina were detected in different kinds of AD transgenic mice at various ages. In Tg2576 transgenic mice, significant infiltration of microglial cells detected by iba-1 and the increased astrocytes activation detected by GFAP in the inner retina were detected as early as 4-month-old mice [73]. In double transgenic APPswe/ PS1M146L mice, microglia was increased in an age-dependent manner, which was in parallel with Aß deposits and TUNEL positive RGC in the GCL. The average percentage of cells in the GCL surrounded by microglial cells increased significantly from 10% in 7.8-month-old to 50% in 27-month-old APPswe/PS1M146L transgenic mice [11]. In another double transgenic APPswe/ PS1∆E9 mice, qualitative evaluation revealed greater immunoreactivity of microglia in 12 to 19 months old transgenic mice when compared to age-matched non-transgenic control[77].

In a rat model mimicking chronic ocular hypertension (COH) [81], Aβ has been reported to be implicated in the development of RGC apoptosis in glaucoma. Increased intracellular Aβ in

APPswe/PS1∆E9 mice [11].

164 Glaucoma - Basic and Clinical Aspects

this transgenic mice line [80].

**3.5. Glial reaction in AD retina**

**4. β-Amyloid peptide and glaucoma**

**4.1. Aβ in animal models mimic glaucoma**

**3.4. Deposition of hyperphosphorylated tau in the retina**

#### **5.1. Tau in the retina of glaucoma patient**

In aged retina (49-87 year-old human), there is a positive correlation between age and number of tau-positive RGCs. Diffuse immunoreactivity of tau was found in the INL, while aggregated tau was found within the cytoplasm of photoreceptor cells in patients older than 63-years-old [93]. Total tau is present in the INL and IPL but much reduced in glaucomatous retina. On the other hand, phosphorylated Tau (pTau) recognized by monoclonal antibody-AT8 is detected in glaucomatous retina at the outer border of the INL and occasionally in the IPL. It has also been found that pTau was localized in horizontal cells labeled by cell marker-parvalbumin [94]. The distribution of tau in the normal aged (Fig. 2A) and glaucomatous retina (Fig. 2B) is summarized in Figure 2. The decrease of total Tau and accumulation of pTau in the glaucom‐ atous retina support the hypothesis showing that glaucoma shares pathways with AD. This is consistent with previous reports showing an increased incidence of primary open-angle glaucoma among AD patients. Recent evidence also indicates that altered cerebrospinal fluid (CSF) circulatory dynamics can reduce the clearance of both Aβ and tau. Altered CSF circula‐ tory dynamics can reduce clearance of neurotoxin along the optic nerve in the subarachnoid space; leading to deposition of tau and other toxic molecules which ultimately result in glaucoma progression[94].

**5.2. Tau in animal models mimic glaucoma**

deserves further evaluation.

**6. Future therapy**

In human glaucoma (chronic ocular hypertension), decreased total Tau and increased phos‐ phorylated tau (pTau) are reported when compared to the age control group [94]. In animal models mimicking acute ocular hypertension, the loss of tau is evident even at earlier stages when the outer layer of the retina is mostly intact [95]. Acute ocular hypertension was induced for 1 hour by elevation of IOP to 120 mm Hg. The loss of tau proteins in the retina has been shown to occur from as early as 4 hours to over 7 days after induction of acute ocular hyper‐ tension. Proteolysis of tau has been suggested contributing to the pathogenesis of neuronal cell death, correlating with an increase in calcium, followed by activation of calpain. Calpaininduced conversion of p35 to p25 and activation of cdk5 are also involved in the RGC loss. There is no direct evidence about increase of pTau. However, it is indirectly evident by the upregulation of the relevant kinase, cdk5, and the regulatory protein, p35/p25. One justification for the failure to detect pTau is that tau protein is cleaved by calpain before detection is possible [95]. Another justification is that this acute elevation of ocular hypertension actually blocks the retinal blood supply at 120 mmHg IOP. This is an ischemia/reperfusion model which may cause neuronal cell hypoxia. Under hypoxic conditions, similar changes have also been reported. In rat retinas treated with hypoxic conditions, it has been found that immunoreac‐ tivity of tau is almost completely lost in retinas within 5 hours; however, the proteolytic products of tau remain detectable [96]. The changes of Tau proteins in the chronic ocular hypertension model which mimic glaucoma over a relative long and slow degenerative period

Progressive Neurodegeneration of Retina in Alzheimer's Disease — Are β-Amyloid Peptide…

http://dx.doi.org/10.5772/53428

167

Increasing lines of evidence have demonstrated common pathological findings in both AD and glaucomatous retinal degeneration. Neuronal losses, inflammatory responses, accumulation of Aβ and pTau deposition are important pathological factors found in the brain and the retina [94], [97]. However, the correlation among Aβ deposits, pTau formation and the retinal degeneration is limited to histological level. The pathological mechanisms have not been comprehensively investigated. Questions like what are the mechanisms triggered by Aβ and

As part of the CNS, the similarity between the brain and the retina allows the exchange of knowledge in terms of pathological mechanisms and therapeutic intervention. Mitochondrial dysfunction discussed above is one of the pathophysiological changes in both AD and retinal degeneration [3], [98]. The discovery of significant involvement of double-stranded RNAdependent protein kinase (PKR) in the apoptosis of neurons in postmortem AD brain and in experimental studies is another good example [99]-[101]. Years after our report of the PKR in AD, PKR has also been proved to play important roles in neuronal apoptosis of RGCs in endoplasmic reticulum (ER) stress-induced retinal neuronal loss [102]. Neuroprotective agents found from *in vitro* AD research can also be applied to eye research. Our Studies on wolfberry, *Lycium barbarum*, an anti-aging herb, can be a good example. In primary neuronal culture,

tau to cause retinal degeneration are still waiting for answers.

**Figure 1. Chiu et al., 2012 Figure 2.** Diagram summarizing the literature reporting on the distribution of tau in the retina of normal people (A) and glaucomatous patient (B). The background is a cross semi-thin section showing the layered structure of the retina. *Ovals labelled 'Tau'* represent expression of total tau. *Cloudy labelled 'Tau'* represent tau aggregates. *Sparckle labelled 'pTau'* represent expression of abnormal phosphorylated tau. NFL: nerve fiber layer, RGCL: retinal ganglion cell layer, IPL: inner plexiform layer, INL: inner nuclear layer, OPL: outer plexiform layer, ONL: outer nuclear layer, RPE: retinal pig‐ ment epithelium.

#### **5.2. Tau in animal models mimic glaucoma**

tau was found within the cytoplasm of photoreceptor cells in patients older than 63-years-old [93]. Total tau is present in the INL and IPL but much reduced in glaucomatous retina. On the other hand, phosphorylated Tau (pTau) recognized by monoclonal antibody-AT8 is detected in glaucomatous retina at the outer border of the INL and occasionally in the IPL. It has also been found that pTau was localized in horizontal cells labeled by cell marker-parvalbumin [94]. The distribution of tau in the normal aged (Fig. 2A) and glaucomatous retina (Fig. 2B) is summarized in Figure 2. The decrease of total Tau and accumulation of pTau in the glaucom‐ atous retina support the hypothesis showing that glaucoma shares pathways with AD. This is consistent with previous reports showing an increased incidence of primary open-angle glaucoma among AD patients. Recent evidence also indicates that altered cerebrospinal fluid (CSF) circulatory dynamics can reduce the clearance of both Aβ and tau. Altered CSF circula‐ tory dynamics can reduce clearance of neurotoxin along the optic nerve in the subarachnoid space; leading to deposition of tau and other toxic molecules which ultimately result in

**B. Glaucomatous retina**

**Tau**

**pTau**

**Tau**

**pTau pTau**

**pTau**

glaucoma progression[94].

166 Glaucoma - Basic and Clinical Aspects

**RPE**

ment epithelium.

**ONL**

**INL**

**IPL**

**RGCL NFL**

**OPL**

**A. Normal aged retina**

**Tau**

**Tau**

**Tau Tau**

**Tau**

**Tau**

**Tau Tau**

**Figure 1. Chiu et al., 2012 Figure 2.** Diagram summarizing the literature reporting on the distribution of tau in the retina of normal people (A) and glaucomatous patient (B). The background is a cross semi-thin section showing the layered structure of the retina. *Ovals labelled 'Tau'* represent expression of total tau. *Cloudy labelled 'Tau'* represent tau aggregates. *Sparckle labelled 'pTau'* represent expression of abnormal phosphorylated tau. NFL: nerve fiber layer, RGCL: retinal ganglion cell layer, IPL: inner plexiform layer, INL: inner nuclear layer, OPL: outer plexiform layer, ONL: outer nuclear layer, RPE: retinal pig‐ In human glaucoma (chronic ocular hypertension), decreased total Tau and increased phos‐ phorylated tau (pTau) are reported when compared to the age control group [94]. In animal models mimicking acute ocular hypertension, the loss of tau is evident even at earlier stages when the outer layer of the retina is mostly intact [95]. Acute ocular hypertension was induced for 1 hour by elevation of IOP to 120 mm Hg. The loss of tau proteins in the retina has been shown to occur from as early as 4 hours to over 7 days after induction of acute ocular hyper‐ tension. Proteolysis of tau has been suggested contributing to the pathogenesis of neuronal cell death, correlating with an increase in calcium, followed by activation of calpain. Calpaininduced conversion of p35 to p25 and activation of cdk5 are also involved in the RGC loss. There is no direct evidence about increase of pTau. However, it is indirectly evident by the upregulation of the relevant kinase, cdk5, and the regulatory protein, p35/p25. One justification for the failure to detect pTau is that tau protein is cleaved by calpain before detection is possible [95]. Another justification is that this acute elevation of ocular hypertension actually blocks the retinal blood supply at 120 mmHg IOP. This is an ischemia/reperfusion model which may cause neuronal cell hypoxia. Under hypoxic conditions, similar changes have also been reported. In rat retinas treated with hypoxic conditions, it has been found that immunoreac‐ tivity of tau is almost completely lost in retinas within 5 hours; however, the proteolytic products of tau remain detectable [96]. The changes of Tau proteins in the chronic ocular hypertension model which mimic glaucoma over a relative long and slow degenerative period deserves further evaluation.
