Ratnayaka, J. Arjuna, Lynn, Savannah A., Pandi, Sudha Priya Soundara, Sanchez-Bretano, Aida, Muir, Anna Marie, Parker, Lidia, Chatelet, David S., Newall, Tutte, Keeling, Eloise, Smyth, Neil R., Self, James E., Lee, Helena, Lotery, Andrew J. and Scott, Jenny A. (2025) Studies in the 5xFAD mouse retina reveal chronic Amyloid-beta mediated effects, providing new insights into complex retinopathies. Investigative Ophthalmology & Visual Science, 66 (8), [1180].
Abstract
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.
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.
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.
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.
This abstract was presented at the 2025 ARVO Annual Meeting, held in Salt Lake City, Utah, May 4-8, 2025.
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