Abstract
Amyloid-β (Aβ) accumulations have been identified in the retina for neurodegeneration-associated disorders like Alzheimer’s disease (AD), glaucoma, and age-related macular degeneration (AMD). Elevated retinal Aβ levels were associated with progressive retinal neurodegeneration, elevated cerebral Aβ accumulation, and increased disease severity with a decline in cognition and vision. Retinal Aβ accumulation and its pathological effects were demonstrated to occur prior to irreversible neurodegeneration, which highlights its potential in early disease detection and intervention. Using the retina as a model of the brain, recent studies have focused on characterizing retinal Aβ to determine its applicability for population-based screening of AD, which warrants a further understanding of how Aβ manifests between these disorders. While current treatments directly targeting Aβ accumulations have had limited results, continued exploration of Aβ-associated pathological pathways may yield new therapeutic targets for preserving cognition and vision. Here, we provide a review on the role of retinal Aβ manifestations in these distinct neurodegeneration-associated disorders. We also discuss the recent applications of retinal Aβ for AD screening and current clinical trial outcomes for Aβ-associated treatment approaches. Lastly, we explore potential future therapeutic targets based on overlapping mechanisms of pathophysiology in AD, glaucoma, and AMD.
Highlights
Accumulation of amyloid-β (Aβ) in the retinal layers has been implicated as a key overlapping feature between three neurodegeneration-associated disorders that have affected millions of older adults worldwide: Alzheimer’s disease (AD), glaucoma, and age-related macular degeneration (AMD)
At the various intra-retinal layers, post mortem human studies showed Aβ deposits above the retinal pigmental epithelium (RPE) and located in the inner retina associated with neuronal loss especially within the ganglion cell layer (GCL), inner nucleus layer (INL), and inner plexiform layer (IPL) (Figure 1), similar to what was described in AD transgenic mice studies [6,30,45,46]
Several Aβ-associated effects appear to be overlapping between AD, glaucoma, and AMD including an increase in the inflammatory pathways, oxidative stress, cytoskeletal disruption, synaptic remodeling, and vascular alterations (Figure 3)
Summary
Accumulation of amyloid-β (Aβ) in the retinal layers has been implicated as a key overlapping feature between three neurodegeneration-associated disorders that have affected millions of older adults worldwide: Alzheimer’s disease (AD), glaucoma, and age-related macular degeneration (AMD). In AD, accumulation of Aβ in the central nervous system (CNS) has been suggested to induce neurodegeneration especially in the hippocampus leading to progressive loss of cognitive function [4]. Aβ has been identified to be associated with increased retinal ganglion cell (RGC) susceptibility to elevated IOP and purposed to induce RGC apoptosis and optic nerve (ON) degeneration [7]. Advanced AMD prevalence was doubled in AD patients in comparison to controls This association was not obvious after correcting for shared risk factors such as age, presence of an apolipoprotein E allele, and smoking [17]. We evaluate existing findings of clinical trials and discuss potential retinal Aβ-associated mechanisms that may provide novel targets for therapeutic interventions
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