A longitudinal study of the 5xFAD mouse retina delineates Amyloid beta (Aβ)-mediated retinal pathology from age-related changes.

backgroundAge-related macular degeneration (AMD) is the commonest cause of irreversible blindness in developed societies. AMD coincides with advanced age to which genetic and lifestyle factors contribute additional risks. High levels of the Alzheimer's-linked Amyloid beta (Aβ) proteins are correlated with aged/AMD retinas. To delineate the role of Aβ in retinopathy from age-related changes, we used transgenic 5xFAD mice in a longitudinal study to recapitulate the aged/AMD Aβ-burden of the human retina.

methodsMice were genotyped to exclude the retinal degeneration alleles Pde6b

resultsAge-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.

conclusionsChronic Aβ exposure led to the earlier development of retinopathy-linked features, the identification of which advances our understanding of how Aβ contributes to multifaceted 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.