Dataset Information

Amyloid Beta Immunoreactivity in the Retinal Ganglion Cell Layer of the Alzheimer's Eye.

ABSTRACT: Alzheimer's disease (AD) is the most prevalent form of dementia, accounting for 60-70% of all dementias. AD is often under-diagnosed and recognized only at a later, more advanced stage, and this delay in diagnosis has been suggested as a contributing factor in the numerous unsuccessful AD treatment trials. Although there is no known cure for AD, early diagnosis is important for disease management and care. A hallmark of AD is the deposition of amyloid-? (A?)-containing senile neuritic plaques and neurofibrillary tangles composed of hyperphosporylated tau in the brain. However, current in vivo methods to quantify A? in the brain are invasive, requiring radioactive tracers and positron emission tomography. Toward development of alternative methods to assess AD progression, we focus on the retinal manifestation of AD pathology. The retina is an extension of the central nervous system uniquely accessible to light-based, non-invasive ophthalmic imaging. However, earlier studies in human retina indicate that the literature is divided on the presence of A? in the AD retina. To help resolve this disparity, this study assessed retinal tissues from neuropathologically confirmed AD cases to determine the regional distribution of A? in retinal wholemounts and to inform on future retinal image studies targeting A?. Concurrent post-mortem brain tissues were also collected. Neuropathological cortical assessments including neuritic plaque (NP) scores and cerebral amyloid angiopathy (CAA) were correlated with retinal A? using immunohistochemistry, confocal microscopy, and quantitative image analysis. A? load was compared between AD and control (non-AD) eyes. Our results indicate that levels of intracellular and extracellular A? retinal deposits were significantly higher in AD than controls. Mid-peripheral A? levels were greater than central retina in both AD and control eyes. In AD retina, higher intracellular A? was associated with lower NP score, while higher extracellular A? was associated with higher CAA score. Our data support the feasibility of using the retinal tissue to assess ocular A? as a surrogate measure of A? in the brain of individuals with AD. Specifically, mid-peripheral retina possesses more A? deposition than central retina, and thus may be the optimal location for future in vivo ocular imaging.

SUBMITTER: Lee S

PROVIDER: S-EPMC7412634 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Amyloid Beta Immunoreactivity in the Retinal Ganglion Cell Layer of the Alzheimer's Eye.

Lee Sieun S Jiang Kailun K McIlmoyle Brandon B To Eleanor E Xu Qinyuan Alis QA Hirsch-Reinshagen Veronica V Mackenzie Ian R IR Hsiung Ging-Yuek R GR Eadie Brennan D BD Sarunic Marinko V MV Beg Mirza Faisal MF Cui Jing Z JZ Matsubara Joanne A JA

Frontiers in neuroscience 20200731

Alzheimer's disease (AD) is the most prevalent form of dementia, accounting for 60-70% of all dementias. AD is often under-diagnosed and recognized only at a later, more advanced stage, and this delay in diagnosis has been suggested as a contributing factor in the numerous unsuccessful AD treatment trials. Although there is no known cure for AD, early diagnosis is important for disease management and care. A hallmark of AD is the deposition of amyloid-β (Aβ)-containing senile neuritic plaques an ...[more]

PMID: 32848548

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Project description:Neuropathological hallmarks of Alzheimer's disease (AD) include pathogenic accumulation of amyloid-β (Aβ) peptides and age-dependent formation of amyloid plaques in the brain. AD-associated Aβ neuropathology begins decades before onset of cognitive symptoms and slowly progresses over the course of the disease. We previously reported discovery of Aβ deposition, β-amyloidopathy, and co-localizing supranuclear cataracts (SNC) in lenses from people with AD, but not other neurodegenerative disorders or normal aging. We confirmed AD-associated Aβ molecular pathology in the lens by immunohistopathology, amyloid histochemistry, immunoblot analysis, epitope mapping, immunogold electron microscopy, quantitative immunoassays, and tryptic digest mass spectrometry peptide sequencing. Ultrastructural analysis revealed that AD-associated Aβ deposits in AD lenses localize as electron-dense microaggregates in the cytoplasm of supranuclear (deep cortex) fiber cells. These Aβ microaggregates also contain αB-crystallin and scatter light, thus linking Aβ pathology and SNC phenotype expression in the lenses of people with AD. Subsequent research identified Aβ lens pathology as the molecular origin of the distinctive cataracts associated with Down syndrome (DS, trisomy 21), a chromosomal disorder invariantly associated with early-onset Aβ accumulation and Aβ amyloidopathy in the brain. Investigation of 1249 participants in the Framingham Eye Study found that AD-associated quantitative traits in brain and lens are co-heritable. Moreover, AD-associated lens traits preceded MRI brain traits and cognitive deficits by a decade or more and predicted future AD. A genome-wide association study of bivariate outcomes in the same subjects identified a new AD risk factor locus in the CTNND2 gene encoding δ-catenin, a protein that modulates Aβ production in brain and lens. Here we report identification of AD-related human Aβ (hAβ) lens pathology and age-dependent SNC phenotype expression in the Tg2576 transgenic mouse model of AD. Tg2576 mice express Swedish mutant human amyloid precursor protein (APP-Swe), accumulate hAβ peptides and amyloid pathology in the brain, and exhibit cognitive deficits that slowly progress with increasing age. We found that Tg2576 trangenic (Tg+) mice, but not non-transgenic (Tg-) control mice, also express human APP, accumulate hAβ peptides, and develop hAβ molecular and ultrastructural pathologies in the lens. Tg2576 Tg+ mice exhibit age-dependent Aβ supranuclear lens opacification that recapitulates lens pathology and SNC phenotype expression in human AD. In addition, we detected hAβ in conditioned medium from lens explant cultures prepared from Tg+ mice, but not Tg- control mice, a finding consistent with constitutive hAβ generation in the lens. In vitro studies showed that hAβ promoted mouse lens protein aggregation detected by quasi-elastic light scattering (QLS) spectroscopy. These results support mechanistic (genotype-phenotype) linkage between Aβ pathology and AD-related phenotypes in lens and brain. Collectively, our findings identify Aβ pathology as the shared molecular etiology of two age-dependent AD-related cataracts associated with two human diseases (AD, DS) and homologous murine cataracts in the Tg2576 transgenic mouse model of AD. These results represent the first evidence of AD-related Aβ pathology outside the brain and point to lens Aβ as an optically-accessible AD biomarker for early detection and longitudinal monitoring of this devastating neurodegenerative disease.

Dataset Information

Amyloid Beta Immunoreactivity in the Retinal Ganglion Cell Layer of the Alzheimer's Eye.

Publications

Amyloid Beta Immunoreactivity in the Retinal Ganglion Cell Layer of the Alzheimer's Eye.

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