A timeline of structural and functional consequences to ipRGCs in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects cognitive, sensory and motor systems, including the visual system and has a significant impact on autonomy and quality of life. Emerging evidence suggests that visual system abnormalities may enable early detection and monitoring for AD, appearing before cognitive symptoms. Intrinsically photosensitive retinal ganglion cells (ipRGCs or mRGCs) are among the first neurons affected in AD. This study investigates the structural and functional changes in ipRGCs during aging. ipRGC and retinal ganglion cell (RGC) degeneration were assessed using immunohistological analyses of retinal wholemounts of the 3xTg-AD mouse model. Behavioral changes were analyzed using light aversion with and without pupil dilation, contrast sensitivity function across five spatial frequencies, and pupillary light reflex (PLR) at three light levels. Changes in ipRGC dendritic varicosities begin between 4-8 months followed by degeneration of other RGC types by 12-16 months of age. Alterations in light aversion were observed at both 6 and 12 months with no alterations in contrast sensitivity function or PLR. Sex-specific differences in disease progression were detected in RGC degeneration. Our findings support the hypothesis that ipRGC dysfunction occurs early in AD and precedes cognitive decline. These findings are similar to ipRGC degeneration previously observed in postmortem human AD retinas, and thus provides a valuable model for studying the mechanism of degeneration and identifying potential behavior changes that might serve as early biomarkers in AD.