Abstract
Purpose :
Age-related macular degeneration (AMD) is a common cause of vision loss with few models available to elucidate disease pathomechanism and test novel therapeutics. The turquoise killifish (N. furzeri) is an accelerated ageing model that naturally develops age-related neurodegeneration and vision loss. We assessed the cone-rich killifish retina for age-related changes and AMD-like pathologies to determine whether ageing retinal disease in killifish is similar to AMD.
Methods :
GRZ strain turquoise killifish eyes were collected at various ages throughout their lifecycle, from young adult (6-week-old) to geriatric (24-week-old; end of lifespan) stages. For transcriptomic analysis, retinas were dissected and sent for RNA-sequencing at 6, 12, and 18 weeks. For histological assessment, eyes were cryosectioned and retinal features labelled via immunohistochemistry or histological stains.
Results :
We previously identified transcriptional dysregulation in the ageing killifish retina via bulk and single-cell RNA-sequencing. We determined that aged killifish have altered expression of genes related to AMD-related processes, such as oxidative stress, metabolism, and inflammation, including increased htra1b and apoeb expression. Coinciding with these findings, aged killifish had subretinal deposits by 18 weeks. The deposits were concentrated in the central retina, with few or no deposits in peripheral retina. Deposits stained for neutral lipids and a subset of deposits also stained for oxidised phospholipids, akin to drusen in AMD patient eyes. Oxidised phospholipids can indicate oxidative stress and trigger an immune response. Consistently, old killifish retinas appeared to have increased microglia in the central retina compared to young retinas. Areas with subretinal deposits had an abundance of microglia in the subretinal space. Subsets of photoreceptor outer segments in aged killifish had opsin mislocalisation to the inner segment and cell body. Additionally, the retinal pigment epithelium in aged retinas appeared pale compared to young retinas, which may suggest stress or cell loss.
Conclusions :
Ageing turquoise killifish naturally develop hallmark features of AMD, including subretinal deposits and inflammation. Killifish are an exciting novel model of ageing retinal disease that can be further utilised to study the mechanisms underlying age-related vision loss and test potential therapeutic strategies.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.