Elevated Intraocular Pressure Induces Amyloid-β Deposition and Tauopathy in the Lateral Geniculate Nucleus in a Monkey Model of Glaucoma

Yan, Zhichao; Liao, Huanquan; Chen, Hongrui; Deng, Shuifeng; Jia, Yu; Deng, Caibin; Lin, Jintian; Ge, Junbo; Zhuo, Yehong

doi:10.1167/iovs.17-22312

Cited by 44 publications

(44 citation statements)

References 54 publications

(61 reference statements)

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“…However, visual impairments have also been described in AD patients as reflected by the reduction of visual acuity, contrast sensitivity, color vision, visual field and pupillary function (Uhlmann et al, 1991 ; Hutton et al, 1993 ; Gómez-Tortosa et al, 1996 ; Whittaker et al, 2002 ). Visual deficits may involve neuronal cell degeneration in the brain (Yan et al, 2017 ) and in the retina. Indeed, amyloid-β (Aβ) deposits and neurofibrillary tangles (NFTs) containing hyperphosphorylated Tau are classical histopathological features of AD that could also be observed in the retina of patients (Hart et al, 2016 ; Koronyo et al, 2017 ; Kusne et al, 2017 ; van Wijngaarden et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Human Tau Expression Does Not Induce Mouse Retina Neurodegeneration, Suggesting Differential Toxicity of Tau in Brain vs. Retinal Neurons

Rodriguez

Mdzomba

Joly

et al. 2018

Front. Mol. Neurosci.

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The implication of the microtubule-associated protein (MAP) Tau in the ocular manifestations of Alzheimer’s disease (AD) is elusive due to the lack of relevant animal model. However, signs of AD have been reported in the brain of transgenic mice expressing human Tau (hTau). To assess whether hTau is sufficient to induce AD pathogenesis in the retina as well, in the present study, we compared the retinal structure and function of KO mice deprived of Tau (mTKO) with those of transgenic mice expressing hTau. Our results revealed that hTau is particularly abundant in the inner nuclear layer (INL) cells of the retina. By electroretinogram (ERG) recording, light-induced retinal cell activation was not altered in hTau compared with mTKO littermates. Surprisingly, the ERG response mediated by cone photoreceptor stimulation was even stronger in hTau than in mTKO retinae. Immunofluorescent analysis of retinal sections allowed us to observe thicker inner retina in hTau than in mTKO eyes. By Western Blotting (WB), the upregulation of mTOR that was found in hTau mice may underlie retinal structure and function increases. Taken together, our results not only indicate that hTau expression is not toxic for retinal cells but they also suggest that it may play a positive role in visual physiology. The use of hTau may be envisaged to improve visual recovery in ocular diseases affecting the retinal function such as glaucoma or diabetic retinopathy.

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Section: Introductionmentioning

confidence: 99%

Human Tau Expression Does Not Induce Mouse Retina Neurodegeneration, Suggesting Differential Toxicity of Tau in Brain vs. Retinal Neurons

Rodriguez

Mdzomba

Joly

et al. 2018

Front. Mol. Neurosci.

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“…A recent study showed an increased Aβ level in the optic nerve and RGC layer in glaucomatous animal models 21 , 22 , and tauopathy was also detected in the glaucomatous retina 23 . A recent study observed these AD-like pathologies in the lateral geniculate nucleus and primary visual cortex in a chronic hypertensive glaucoma monkey model 24 . However, the results of epidemiological studies are still conflicting.…”

Section: Discussionmentioning

confidence: 92%

“…e ., the progressive loss of neuron structure or function, including AD and PD, is currently recognized as a major public health issue with the aging global population 15 , 16 . There is increasing evidence of neurodegenerative lesions found in AD are also observed in the optic nerve, lateral geniculate nucleus, and visual cortex in glaucoma patients, suggesting that OAG is a neurodegenerative disease of the eye 17 – 24 . Previous experimental and clinical studies have shown close associations between OAG and PD 25 – 27 .…”

Section: Introductionmentioning

confidence: 99%

Association between Open-Angle Glaucoma and the Risks of Alzheimer’s and Parkinson’s Diseases in South Korea: A 10-year Nationwide Cohort Study

Moon

Kim

Park

et al. 2018

Sci Rep

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We aimed to investigate the risks of Alzheimer’s (AD) and Parkinson’s disease (PD) in the 10 years following diagnosis of open-angle glaucoma (OAG) using a nationwide cohort. This propensity score-matched retrospective cohort study included 1,025,340 subjects from the Korean National Health Insurance Service National Sample Cohort database. The OAG group (n = 1,469) included patients who were initially diagnosed with OAG between 2004 and 2007, and the subjects in the comparison group were matched in a 1:5 ratio using propensity scores. Cox regression analyses were performed to investigate the risks of developing AD or PD. The diagnosis of OAG was significantly associated with an increased incidence of AD (hazard ratio [HR] = 1.403, 95% confidence interval [CI] 1.180–1.669, p < 0.001), but not PD (HR = 0.995, 95% CI 0.620–1.595, p = 0.983) after adjusting for possible confounding factors. In subgroup analyses, participants with OAG aged ≥65 years were more likely to develop AD compared with those aged <65 years, and female OAG patients had a greater risk of developing AD than males. Patients diagnosed with OAG have a higher risk of developing AD, but not PD, and the risk differed according to age and sex.

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“…Aβ deposition 29,30,31 Complement activation 6 Neuroinflammation + microglial activation 6 Neuronal cell death 6 Neuroinflammation + microglial activation 6 Neuronal cell death 6 As mentioned before, elevated IOP is common feature and the greatest risk factor for glaucoma. However, a link between glaucoma and AD has been proposed 26 , and the presence of protein deposits characteristic of AD (Aβ and pTau) has been described in the retinas of glaucoma patients 6,27,28 . Moreover, in both diseases comparable Aβ and pTau profiles are observed in the compartments closest to the primary affected tissue.…”

Section: Alzheimer´s Disease Parkinson´s Disease Glaucomamentioning

confidence: 99%

CHAPTER 4. CNS Targets for the Treatment of Retinal Dystrophies: A Win–Win Strategy

Rosa¹,

Hernández‐Sánchez²

2018

Drug Discovery

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As an extension of the central nervous system (CNS), the retina shares with the brain certain developmental, physiological, and pathological characteristics. However, the underlying mechanisms and pathological signs common to neurodegenerative conditions of both the retina and brain have been relatively overlooked. In animal models and in human patients, marked retinal alterations have been demonstrated in Alzheimer´s disease, Parkinson´s disease, and multiple sclerosis, among other pathologies. Furthermore, neurodegeneration of the retina and brain appears to be mediated by similar mechanisms, which include protein aggregation, neuroinflammation, and cell death. Analysis of the retina, which is easily accessible to objective techniques, may therefore constitute an effective tool for the screening and follow-up of CNS neurodegeneration. Moreover, patients with retinal neurodegeneration could potentially benefit from the broad array of pharmacological compounds that have been designed and tested for the treatment of the aforementioned CNS pathologies. Supporting this view, we have shown that GSK-3 inhibitors, which have already been tested in clinical trials to treat several neurodegenerative conditions of the brain, attenuate retinal damage and vision loss in a mouse model of retinitis pigmentosa. Furthermore, systemic proinsulin treatment preserves visual and cognitive function in mouse models of retinitis pigmentosa and precocious aging, respectively.

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Elevated Intraocular Pressure Induces Amyloid-β Deposition and Tauopathy in the Lateral Geniculate Nucleus in a Monkey Model of Glaucoma

Abstract: For the first time to our knowledge, these data collectively establish the existence of hallmark AD-like pathologies in the glaucomatous LGN. Our results may provide new targets for developing research therapies that will enhance neuroprotection in glaucoma patients.

Cited by 44 publications

References 54 publications

Human Tau Expression Does Not Induce Mouse Retina Neurodegeneration, Suggesting Differential Toxicity of Tau in Brain vs. Retinal Neurons

Human Tau Expression Does Not Induce Mouse Retina Neurodegeneration, Suggesting Differential Toxicity of Tau in Brain vs. Retinal Neurons

Association between Open-Angle Glaucoma and the Risks of Alzheimer’s and Parkinson’s Diseases in South Korea: A 10-year Nationwide Cohort Study

CHAPTER 4. CNS Targets for the Treatment of Retinal Dystrophies: A Win–Win Strategy

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