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Retinal Amyloid-β: Comparison
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Please note this is a comparison between Version 3 by Camila Xu and Version 5 by Conner Chen.

Amyloid-β (Aβ) is a 39–43 amino acid protein peptide that originates from the amyloidogenic pathway with cleavage of a transmembrane glycoprotein, amyloid precursor protein (APP), by β- and γ-secretase. Retinal Aβ accumulations in neurodegeneration-associated disorders like Alzheimer's disease, glaucoma, and age-related macular degeneration have been extensively studied and regarded as an overlapping pathological feature between these disorders with no successful cure. 

  • amyloid-β
  • Alzheimer’s disease
  • glaucoma
  • age-related macular degeneration

1. Introduction

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). All three disorders are chronic, age-related disorders with no known cure and can lead to irreversible disability [1][2][3]. 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]. Visual disturbances and retinal Aβ accumulations have been reported in patients with early or even preclinical AD with retinal Aβ deposits appearing to be detected earlier than neurodegeneration and associated cerebral Aβ in AD mice models [5][6]. Similarly, glaucoma is characterized by retinal neurodegeneration most commonly in relation to elevated intraocular pressure (IOP). In glaucoma animal models, 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]. For AMD, severe central vision loss occurs after disruption of the retinal pigmental epithelium (RPE) with the formation of drusen, which leads to retinal neuronal degeneration, especially in the photoreceptor cells (PRC) [8]. Through postmortem studies and AMD mice models, Aβ deposits have been identified inside RPE cells and drusen that has been suggested to be associated with AMD progression [8][9][10].

Epidemiological connections have also been determined between AD, glaucoma, and AMD. Both glaucoma and AMD also appear to be related to a decline in cognitive function, although it is unclear if subjects had other undetected co-existing underlying pathologies [11][12][13][14]. Patients who have glaucoma and AMD have been associated with an increased risk for AD [15]. Similarly, AD patients have an increased prevalence for glaucoma with glaucoma observed in 7–24% of AD patients in comparison to 4–10% of healthy controls [16]. Advanced AMD prevalence was also doubled in AD patients in comparison to controls. However, this association was not obvious after correcting for shared risk factors such as age, presence of an apolipoprotein E allele, and smoking [17]. Since Aβ accumulation in the retina is considered to be a mechanistic link between these degenerative diseases, this warrants further exploration and cross-examination of the pathophysiological role of retinal Aβ and its implications for disease monitoring and treatment.

2. Aβ in the Retina

As a developmental outgrowth of the diencephalon, the retina is the innermost layer of the eye that shares structural and pathophysiological pathways with the CNS including a connection between the microvasculature and axonal projections [18], and contain a diverse population of neurons [19][20]. The exact role of Aβ in the eye is still unknown, although Aβ has been suggested to have an anti-microbial effect in the brain, which may also apply to its role in the retina [21]. Aβ is a 39–43 amino acid protein peptide that originates from the amyloidogenic pathway with cleavage of a transmembrane glycoprotein, amyloid precursor protein (APP), by β- and γ-secretase [22][23]. APP is expressed in various tissues including the retina and appears to support synaptogenesis and neuronal development and survival [23]. Through the non-amyloidogenic pathway, proteolytic processing of APP by α- and γ-secretase generates soluble amyloid precursor protein (sAPPα), which has been shown to have a neuroprotective function in the retina [24]. Within the retina during pathological states, these Aβ monomers have been observed to spontaneously aggregate into dimers, trimers, and oligomers [22]. Through hyperspectral Raman imaging, soluble Aβ oligomers have been demonstrated to self-assemble into beta-pleated sheets and form structures such as protofibrils, fibrils, and insoluble amyloid plaques through hydrogen bonding between peptide bonds of parallel oligomers [22][25]. Similar to Aβ in the brain, in murine models [26], retinal Aβ oligomers have been shown to be more neurotoxic than fibrils with smaller oligomers formations associated with increased amounts of neuronal loss. Fibrillar structures have also been observed to shift to oligomer structures in vivo [23]. The main alloforms of Aβ in the retina are Aβ42 and Aβ40 [22]. Aβ42 has been observed to be more neurotoxic in the retina even though Aβ40 has been more commonly found throughout the retina for these neurodegeneration-associated disorders. The exact Aβ42/Aβ40 ratios in the retina will need to be determined in future studies [23][27].

3. Alzheimer’s Disease

Around 50 million older adults have been diagnosed with dementia worldwide and AD is the most common cause of dementia [28]. Aβ deposits that form insoluble plaques in the brain regions have been purposed to be the principal source of neurotoxicity that leads to brain atrophy and cognitive decline. The highest amyloid load has usually been observed in the hippocampus [4]. Due to the developmental, structural, and pathological connections between the retina and the CNS and the accessibility of the neuroretina for non-invasive imaging, recent studies have explored retinal Aβ as a potential biomarker for the assessment of cerebral Aβ and AD progression [29][30][31][32][33][34]. Through positron emission tomography (PET) imaging cerebral Aβ accumulation may be detected as early as 20 years before cognitive decline [30][35]. In a meta-analysis using PET imaging, Aβ accumulation was identified in 10–44% of subjects with normal cognition, compared to 27–71% of patients with mild cognitive impairment (MCI) [36]. In a separate meta-analysis, Aβ accumulations were found in 68–97% of AD patients [37]. While PET imaging has been successful in characterizing cerebral Aβ plaques, it is inaccessible for much of the population, costly, invasive, and not suitable for population-based screening for AD risk [30][31]. This warrants further characterization of Aβ in the retinas of AD patients to potentially allow early diagnosis and intervention of AD, which can be crucial for slowing the process of neurodegeneration and preserving cognitive function [38].

3.1. Aβ Presentation in the Retinal Enface View and Intra-Retinal Layer View for AD

For post-mortem studies with wholemount retinas and curcumin-based in-vivo imaging studies, increased retinal Aβ was detected in AD patients in comparison to age-matched normal controls (Figure 1). Various Aβ structures were identified including fibrils, protofibrils, and potentially oligomers through transmission electron microscopy of retinal tissue [1][30][39]. Aβ accumulations included both intracellular cyto-deposits and extracellular deposits described by different studies to range from under 5 µm to over 20 µm with larger Aβ deposits resembling a more classical cerebral Aβ plaque [30][39]. Across the plane of the retinal tissue, more Aβ accumulations were identified in the far-peripheral and mid-peripheral of the superior temporal quadrant than in the central retina [30][39][40][41]. Aβ deposits in the superior quadrant were associated with cerebral Aβ deposits, especially in the primary visual cortex (V1) [30]. While the mechanism behind a more superior focused accumulation is currently unknown, this phenomenon may explain the thinning that has been observed in the superior quadrant of the retinal nerve fiber layer, ganglion cell layer (GCL), and inner plexiform layer (IPL), which is made up of the RGC cell bodies and axons [42][43]. Interestingly, early AD patients have predominantly inferior loss of the visual field, which corresponds to the involvement of the superior quadrant of the retina [42][44]. Furthermore, the peripheral loss of RGCs with visual field loss has a similar pattern as what is observed in glaucoma [40].

At the various intra-retinal layers, post mortem human studies showed Aβ deposits above the RPE and located in the inner retina associated with neuronal loss especially within the GCL, inner nucleus layer (INL), and IPL (Figure 1), similar to what was described in AD transgenic mice studies [6][30][45][46]. These findings are in line with Aβ-associated inner retina degeneration and especially RGC dysfunction as detected through decreased pattern electroretinogram responses and positive scotopic threshold response amplitudes found in AD transgenic mice, which may explain the visual disturbances observed in AD patients [1][6][19]. Additionally, increased Aβ-induced toxicity has been suggested to be associated with elevated levels of proteasomal proteins. Decreased levels of proteins associated with synthesis and elongation (e.g., elongation factor EEF1E1) were also observed in the retinas of older AD mice model retinas [47]. In mice models with Aβ positive inner retinas, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive neuronal cells were detected supporting the association between Aβ accumulation and neurodegeneration [1][48]. This association may explain why in vivo human and animal studies show inner retinal layer thinning, especially in the GCL, and loss of ON volume and density [1][18][49]. Intracellular and extracellular Aβ accumulations were the most concentrated in the RGC of the GCL layer (Figure 2) [30][39]. These deposits were also identified inside and surrounding the melanopsin retinal ganglion cells (mRGC), which may be the cause of the mRGC loss and abnormal mRGC morphology in postmortem AD retinas. mRGCs are intrinsically photosensitive and are essential for circadian photoentrainment [40]. In glaucoma, mRGC degeneration was found to induce circadian rhythm dysfunction, which was associated with sleep disturbances [50]. Indeed, mild-moderate AD patients have been associated with reduced sleep efficiency and rest-activity circadian dysfunction, which may be in part associated with the observed Aβ accumulation in mRGCs [40]. Additional research will be necessary to determine if Aβ-induced mRGC degeneration can directly affect sleep efficiency in AD patients or if other underlying mechanisms are involved. Similarly, in both MCI and AD postmortem retinas, Aβ accumulations have been detected in and around pericytes [51], which were found within the endothelial walls of capillaries. Pericytes regulate blood flow and maintain the blood retinal barrier (BRB) and blood brain barrier (BBB) [52]. These accumulations were found to be associated with pericyte loss and possibly contribute to the retinal vascular changes that have been observed in AD patients [51][53].

3.2. Relationship between Aβ in the Retina and Brain for AD

Post-mortem and in vivo human studies have also shown an association between retinal Aβ deposits and cerebral structural and functional changes [29][30]. In addition to a positive correlation between supertemporal retinal Aβ42 load and cerebral Aβ, worse neuropathy cortical assessment scores like neuritic plaque score and cerebral amyloid angiopathy (CAA) were correlated to increased retinal Aβ load in AD retinal whole mounts [30][39]. Aβ accumulations positively correlated between ultra-centrifuged homogenates of the hippocampus and the retina [54]. This relationship may explain why retinal Aβ count in the superotemporal retina subregions was inversely correlated with hippocampal volume for both MCI and AD patients in vivo [29]. To note, loss of hippocampal volume has been related to a decrease in executive dysfunction and memory impairment [55][56]. Proximal and mid-periphery retinal Aβ count and surface area were also greater in patients with increased cognitive decline as indicated by low cognitive assessment scores for both MCI and AD patients [29]. These associations support the hypothesis that Aβ-associated neurotoxicity has an associated pathological effect on the retina and brain. However, it is still unclear if accumulated retinal Aβ causes the observed neurodegeneration or if it is simply a downstream product of other disease mechanisms occurring in the CNS. Based on the retinal and cerebral Aβ associations, it may also be possible that neurodegeneration in both tissues may occur simultaneously and mirror each other during AD disease progression.

Based on its accessibility in vivo and correlation with cerebral Aβ levels, retinal Aβ appears to have the potential to become a promising biomarker for early detection of AD-related cerebral changes and cognitive decline. Several techniques have been purposed for in-vivo detection and screening of retinal Aβ including the use of confocal imaging with curcumin, a non-toxic anti-Aβ fluorescent probe, CRANAD-X probes with near-infrared fluorescent imaging (NIRF), and hyperspectral imaging without the need for ingestion or injection of fluorescent probes [5][29][30][31][32][33][57][58][59]. All methods have been able to identify retinal Aβ in vivo and distinguish AD transgenic mice from wild-type (WT) mice [29][30][31][33]. So far, only confocal imaging with orally ingested curcumin has been tested in humans and was able to distinguish AD patients from controls in addition to establishing correlations between retinal Aβ and cerebral manifestations [29][30]. However, since the largest human sample size was 34 patients, further validation in larger sample sizes will be needed to determine if this method can be applied in population-based screening applications [29]. Additionally, repeatability and longitudinal studies are needed to determine if these observed retinal Aβ deposits can be consistently observed and if they persist or change during the AD disease course. While some differences in the presentation of the retinal Aβ can be found between AD and other diseases like glaucoma and AMD, there is still overlapping between the localizations of Aβ (Figure 2). Future studies will also be needed to better characterize retinal Aβ distribution, manifestation, and population prevalence in AD patients, especially in comparison to other amyloidogenic and age-related retinal diseases like glaucoma and AMD that share similar Aβ-associated manifestations in the retina [1][9][60].

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