The retinal toxicity profile towards assemblies of Amyloid-ß indicate the predominant pathophysiological activity of oligomeric species.

ABSTRACT

Amyloid-ß (Aß), reported as a significant constituent of drusen, was implicated in the pathophysiology of age-related macular degeneration (AMD), yet the identity of the major pathogenic Aß species in the retina has remained hitherto unclear. Here, we examined the in-vivo retinal impact of distinct supramolecular assemblies of Aß. Fibrillar (Aß40, Aß42) and oligomeric (Aß42) preparations showed clear biophysical hallmarks of amyloid assemblies. Measures of retinal structure and function were studied longitudinally following intravitreal administration of the various Aß assemblies in rats. Electroretinography (ERG) delineated differential retinal neurotoxicity of Aß species. Oligomeric Aß42 inflicted the major toxic effect, exerting diminished ERG responses through 30 days post injection. A lesser degree of retinal dysfunction was noted following treatment with fibrillar Aß42, whereas no retinal compromise was recorded in response to Aß40 fibrils. The toxic effect of Aß42 architectures was further reflected by retinal glial response. Fluorescence labelling of Aß42 species was used to detect their accumulation into the retinal tissue. These results provide conceptual evidence of the differential toxicity of particular Aß species in-vivo, and promote the mechanistic understanding of their retinal pathogenicity. Stratifying the impact of pathological Aß aggregation in the retina may merit further investigation to decipher the pathophysiological relevance of processes of molecular self-assembly in retinal disorders.