The complexities underlying age-related macular degeneration: could amyloid beta play an important role?

Abstract

Age-related macular degeneration (AMD) causes irreversible loss of central vision for which there is no effective treatment. Incipient pathology is thought to occur in the retina for many years before AMD manifests from midlife onwards to affect a large proportion of the elderly. Although genetic as well as non-genetic/environmental risks are recognized, its complex aetiology makes it difficult to identify susceptibility, or indeed what type of AMD develops or how quickly it progresses in different individuals. Here we summarize the literature describing how the Alzheimer's-linked amyloid beta (Aβ) group of misfolding proteins accumulate in the retina. The discovery of this key driver of Alzheimer's disease in the senescent retina was unexpected and surprising, enabling an altogether different perspective of AMD. We argue that Aβ fundamentally differs from other substances which accumulate in the ageing retina, and discuss our latest findings from a mouse model in which physiological amounts of Aβ were subretinally-injected to recapitulate salient features of early AMD within a short period. Our discoveries as well as those of others suggest the pattern of Aβ accumulation and pathology in donor aged/AMD tissues are closely reproduced in mice, including late-stage AMD phenotypes, which makes them highly attractive to study dynamic aspects of Aβ-mediated retinopathy. Furthermore, we discuss our findings revealing how Aβ behaves at single-cell resolution, and consider the long-term implications for neuroretinal function. We propose Aβ as a key element in switching to a diseased retinal phenotype, which is now being used as a biomarker for late-stage AMD.

The Diverse Roles of TIMP-3: Insights into Degenerative Diseases of the Senescent Retina and Brain

“…The EMT of RPE cells is associated with the development of sub-retinal fibrosis which contribute to sight loss in AMD; further evidence for the role of oxidative stress and inflammation in retinopathies [118,119]. Aβ, which accumulates in aged eyes and in eyes with AMD [48], is another potential source of retinal inflammation, and has been shown to disrupt the RPE barrier via direct and indirect mechanisms, including elevated production of reactive oxygen species, that results in diminished trans-epithelial resistance and barrier integrity [120,121]. How these processes effect the regulation of ECM components such as TIMP-3 in the aged and diseased retina is still not fully understood.…”

“…Proteins in drusen may be further modified by age-related processes such as oxidative stress [46]. Another drusen constituent is the Alzheimer's-linked Aβ family of misfolding proteins, which is found in high levels in aged donor eyes with moderate-high levels of drusen and in eyes of AMD patients [47,48]. The constituents of drusen are considered to derive from the RPE, photoreceptors and the choroid (endothelial, fibroblast and smooth muscle cells) as well as from serum.…”

“…Early AMD includes structural and physiological changes to the RPE-BrM complex, which is not always associated with sight loss. BrM pathology is a well-established trigger of AMD, which alongside advanced age, includes increased deposition of complement proteins, hydroxyapatite, modified lipids and Aβ amongst others [45,48,[56][57][58]. Alterations to the synthesis and/or activities of TIMP-3 can also be added to this list, as our previous studies identified rare coding TIMP-3 variants (<0.1%) with a >30-fold increase risk of AMD compared to controls [59].…”

Retinal Degeneration and Alzheimer’s Disease: An Evolving Link

“…Retinal degeneration associated with AMD shares several features with AD, including extracellular deposits of Aβ, chronic inflammation, and oxidative stress, the latter partly attributed to the accumulation of iron [ 72 , 73 , 74 , 75 , 76 ]. AMD is typically associated with the accumulation of drusen between the retinal pigment epithelial (RPE) cell layer that forms the outer blood-retinal barrier and the Bruch’s membrane (BM), resulting in dysfunction of the barrier and death of photoreceptor cells.…”

“…Among the various denatured proteins that comprise drusen, Aβ is prominent, suggesting a link with AD [ 77 ]. In addition, inflammation, the accumulation of iron, and oxidative stress play a central role in disease progression [ 74 ]. In a recent study of ~800 cases of AD, a significant positive correlation was noted with the established diagnosis of AMD and recent diagnosis of glaucoma [ 78 ], linking the three conditions.…”