Oligomeric Aβ1-42 Induces an AMD-Like Phenotype and Accumulates in Lysosomes to Impair RPE Function

Abstract

Alzheimer’s disease-associated amyloid beta (Aβ) proteins accumulate in the outer retina with increasing age and in eyes of age-related macular degeneration (AMD) patients. To study Aβ-induced retinopathy, wild-type mice were injected with nanomolar human oligomeric Aβ1-42, which recapitulate the Aβ burden reported in human donor eyes. In vitro studies investigated the cellular effects of Aβ in endothelial and retinal pigment epithelial (RPE) cells. Results show subretinal Aβ-induced focal AMD-like pathology within 2 weeks. Aβ exposure caused endothelial cell migration, and morphological and barrier alterations to the RPE. Aβ co-localized to late-endocytic compartments of RPE cells, which persisted despite attempts to clear it through upregulation of lysosomal cathepsin B, revealing a novel mechanism of lysosomal impairment in retinal degeneration. The rapid upregulation of cathepsin B was out of step with the prolonged accumulation of Aβ within lysosomes, and contrasted with enzymatic responses to internalized photoreceptor outer segments (POS). Furthermore, RPE cells exposed to Aβ were identified as deficient in cargo-carrying lysosomes at time points that are critical to POS degradation. These findings imply that Aβ accumulation within late-endocytic compartments, as well as lysosomal deficiency, impairs RPE function over time, contributing to visual defects seen in aging and AMD eyes.

An Essential Role for Alzheimer’s-Linked Amyloid Beta Oligomers in Neurodevelopment: Transient Expression of Multiple Proteoforms during Retina Histogenesis

“…Second, it remains to be seen whether the retina of humans expresses AβOs in various degenerative pathologies. This possibility is consistent with reports linking Aβ to neurodegenerative disorders of the retina, not only AD [124] but also macular degeneration and glaucoma [124][125][126][127]. In addition, experimental type diabetes in rabbits, another species which has the human Aβ42 sequence, has been shown to induce retina AβOs [128].…”

A High Fat “Western‐style” Diet Induces AMD‐Like Features in Wildtype Mice

“…Furthermore, assessment by full-field ERGs do not always indicate evidence of pathology, even in the presence of focal retinal lesions in AMD-like mouse models. [11] This was also noted in geographic atrophy (GA) AMD patients without multifocal ERG. [29] Animals were euthanized by perfusion fixation and the eyes enucleated immediately, providing the best possible source of freshly preserved tissues for subsequent analysis.…”

“…We have provided additional details on animal welfare related to this procedure in a previous article. [ 11 ]…”

Role of amyloid β-peptide in the pathogenesis of age-related macular degeneration

“… 40 This has also been proved by a new research which found that Aβ accumulates in lysosomes under the circumstances of late-endocytic compartments and damages the function of RPE cells chronically. 49 From this information, self-protection is induced through activating the autophagy-lysosomal pathway in the initial stage of Aβ exposure, 40 rather than in the late stage.…”