Abstract
Purpose :
Amyloid-β (Aβ), a constituent of drusen, was implicated in the pathophysiology of age -related macular degeneration (AMD). Accumulating evidence supports an association between retinal Aβ deposition and compromise of the retinal integrity, yet the major pathogenic Aβ species in the retina and the mechanism of Aβ-mediated neurotoxicity remain unknown. We aimed to investigate the impact of different Aβ species on retinal function and structure in the rat.
Methods :
Wild type rats were treated with intravitreal administration of distinct Aβ assemblies in the right eye, whereas the left eye was treated with the vehicle and served as control. Following the injection, retinal function and structure were studied longitudinally. Electroretinography, retinal histology and immunohistochemistry for Glial Fibrillary Acidic Protein (GFAP), a marker of retinal stress, were compared between treated and fellow eyes. Fluorescence labeling of Aβ species was used to follow their assembly to the retinal tissue, and immunostaining for Aβ characterized the nature of aggregates found in situ.
Results :
Fibrillar (Aβ40, Aβ42) and oligomeric (Aβ42) preparations were synthesized. Assemblies possessed clear hallmarks of ordered amyloid structures based on transmission electron microscopy, spectroscopy and ThT Fluorescence. Electroretinography (ERG) in treated rats demonstrated a differential toxic effect of Aβ species. Oligomeric Aβ42 inflicted the strongest toxic effect, manifesting diminished ERG responses through 30 days post injection. A lesser retinal cytotoxic effect was noted following injection of fibrillar Aβ42, whereas no retinal compromise was recorded in response to Aβ40 fibrils. The toxic effect of Aβ42 organizations was further reflected by retinal glial response in treated eyes, evident by positive GFAP labeling and by internalization of the Aβ assemblies into Müller cells.
Conclusions :
Our results provide conceptual evidence of the retinal toxicity of Aβ in vivo, and promote the mechanistic understanding of the pathogenicity of particular Aβ species. Stratifying the impact of pathological Aβ aggregation in the retina may enhance the understanding of amyloid-mediated retinal neurodegeneration, and may merit further investigation as a therapeutic avenue in AMD.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.