Abstract
Purpose :
Amyloid-beta (Aβ), a family of polypeptides prone to self-assemble into aggregates is a significant component of drusen, thus implicated in age-related macular degeneration (AMD). In a previous study we showed that oligomeric Aβ42 is more retinotoxic compared to fibrillar Aβ42, but a mechanistic overlap was suggested. We further found that fibrillar Aβ42 affected lipid and cholesterol metabolism and membrane raft assembly. Yet, the biologic alterations induced by oligomeric Aβ42 are to be defined. Here, we hypothesized that the retinal effects exerted by oligomeric Aβ42 will share similarity with fibrillar Aβ42 but will include additional pathways mediating the more acute and profound toxicity compared to fibrillar Aβ42.
Methods :
Adult female Sprague-Dawley rats were assigned to oligomeric Aβ42 (n = 8) and control (n = 8) groups. Correspondingly, each rat's right eye was injected intravitreally with oligomeric Aβ42 or vehicle (10μl). The neurosensory retina was extracted 4 days after treatment and 30 days after treatment (n= 4 rats in each group), and transcriptome analysis using RNA-sequencing (RNA-seq) was performed. A Gene Ontology analysis was conducted in R software (R Core Team, Vienna, Austria) using DOSE and enrichplot.
Results :
We found a total of 52 differentially expressed genes of which 31 were up-regulated and 21 were down-regulated in retinas extracted 4 days after oligomeric Aβ42 injection. Pathway analysis showed that similar to the retinal response to fibrillar Aβ42, oligomeric Aβ42 was involved in regulation of cholesterol metabolism. However, in addition, regulation of the adaptive immune system and phagocytosis emerged as activated cascades. Interestingly, a single injection of oligomeric Aβ42 caused upregulation of complement factor H (CFH). At 30 days after oligomeric Aβ42 injection the apoptotic pathway was highly enriched.
Conclusions :
The differential retinotoxicity of oligomeric vs fibrillar Aβ42 may be related to activation of an inflammatory response and dysregulation of phagocytosis. The expression of CFH, strongly associated with AMD risk in human subjects, suggests relevance of Aβ in the disease. Characterizing the downstream effects of different Aβ structures can promote our understanding of the fundamental pathophysiology of Aβ-related retinal degeneration, and may provide insight into potential AMD treatment strategies.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.