Studies in the 5xFAD mouse retina reveal chronic Amyloid-beta mediated effects, providing new insights into complex retinopathies

Purpose: deposition of Alzheimer’s-linked Amyloid beta (Abeta) proteins in the retina is correlated with advanced age and retinal degeneration. To delineate the role of Abeta in retinopathy from age-related changes, we used transgenic 5xFAD/C57BL6 mice in a longitudinal study to recapitulate the Abeta burden in the human retina.<br/><br/>Methods: mice were genotyped to exclude the retinal degeneration alleles Pde6brd1, Pde6brd8, Agouti, Tyr and Oca2. Retinas of 5xFAD and wildtype littermates (97 males/females in total) were longitudinally assessed until 15 months using non-invasive retinal scans: full-field ERG, optokinetic tracking, OCT, funduscopy and fluorescein angiography. Mice were killed at 4, 8 and 15 months, and eyes enucleated for analyses by light/confocal and electron microscopy.<br/><br/>Results: age-related changes included a gradual decline of retinal activity in all mice. Subretinal/drusen-like deposits increased with age, but, like retinal vessel morphology and vessel integrity, showed no differences between cohorts. Diminished PSD95 levels indicated impaired photoreceptor-bipolar connectivity which correlated with age. Ultrastructural imaging showed increased electron-dense granules and undigested outer segments within retinal pigment epithelial cells with age. 5xFAD pathology included significant weight reduction vs. wildtype/littermates, which were pronounced in females. 8 month old 5xFAD mice had diminished A and B waves, though the age-related decline in wildtype mice abolished these subsequently. Visual acuity/function was also reduced in 14 month 5xFAD eyes. OCT revealed thickened photoreceptor nuclei and inner segments in 8 month 5xFAD retinae. Scrutiny of chorioretinal tissues revealed diminished photoreceptor nuclei in 4 month 5xFAD eyes, though differences were abolished as both cohorts aged. From 8 months onwards, 5xFAD mice possessed fewer bipolar cell nuclei.<br/><br/>Conclusions: chronic Abeta exposure led to the earlier development of retinopathy-linked features, the identification of which advances our understanding of how Abeta contributes to complex retinopathies. These were distinguishable from wider age-related changes and non-specific influences of retinal degeneration alleles in 5xFAD mice. Longitudinal analyses revealed sex and age-related limitations and important 3Rs considerations for future studies using 5xFAD mice.<br/><br/>This abstract was presented at the 2025 ARVO Annual Meeting, held in Salt Lake City, Utah, May 4-8, 2025.