Abstract
Purpose :
Age is a primary risk factor for prominent retinopathies like glaucoma and age-related macular degeneration. Susceptibility to age-related retinal neurodegeneration is likely genetically influenced. To better understand and model age-related retinopathies, molecular aging signatures were identified in an array of 9 diverse mouse strains. Among these, wild-derived WSB/EiJ (WSB) mice exhibited a distinct aging signature indicating pronounced photoreceptor loss. Here, we longitudinally characterized retinal aging in WSB mice to assess their utility in modeling age-related photoreceptor degeneration.
Methods :
RNA-sequencing and proteomics were employed to profile retinal aging signatures in an array of genetic backgrounds, including pigmented, wild-derived, and albino mouse strains at 4, 12, and 18M. Subsequently, WSB and B6 mice were subjected to a battery of longitudinal in vivo examinations (n≥18 eyes, both sexes) at 4, 8, 12, and 18M, including fundus exams, optical coherence tomography (OCT), and electroretinograms (ERG). Retinal morphological assessment was performed ex vivo at 4 and 18M (H&E, n≥12 eyes, both sexes). Data were analyzed with two-way ANOVAs with Sidak post-hoc tests and are listed as %difference±SEM where appropriate.
Results :
Multi-omic analyses revealed WSB mice lose photoreceptor-associated transcripts and proteins with age. Fundus exams showed instances of pigmentary loss in WSB retinas (11% at 12M and 36% at 18M; not evident in B6). OCT measurements indicated WSB retinas were 21.9±0.6% thinner than B6 retinas at 4M (p<0.001). B6 retinas had subtle age-related thinning from 4-18M (4.5±0.8%, p=0.021), however, WSB retinas had significantly more age-related thinning (21.4±2.0%, p<0.001), most notably of the outer nuclear layer (ONL; 45.7±3.0%, p<0.001). Histology confirmed degenerated or absent ONLs at 18M, particularly in the central retina. WSB ERG a-wave, b-wave, and oscillatory potential amplitudes were significantly lower than B6 at 4M (47.2±5.7, 59.2±2.5, and 80.2±1.6% respectively, p<0.001), and WSB a-waves declined from 4-18M (53.2±2.6%, p<0.001).
Conclusions :
Here, we provide a multi-omic resource of retinal aging across diverse mice, which can aid in understanding retinal aging and disease. This database identified WSB mice as a potentially novel model of photoreceptor degeneration, which was substantiated and characterized via OCT, H&E, and ERG analyses.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.