Altered photoreceptor metabolism in mouse causes late stage age-related macular degeneration-like pathologies

Significance

The main cause for blindness in the elderly worldwide is age-related macular degeneration (AMD). What causes AMD remains unknown. The high metabolic demands of photoreceptors are thought to contribute to disease pathogenesis, yet whether photoreceptor metabolism differs in individuals with AMD has not been determined. Here, we show that photoreceptor metabolism does differ between diseased and nondiseased individuals. Mimicking the metabolic profile of diseased individuals in mouse resulted in the similar advanced pathologies as those that cause blindness in humans. A disease model with photoreceptors as a contributing factor explains also why AMD affects preferentially the macula; it is the region of highest photoreceptor density. The data might open new avenues to study the role of PRs in disease pathogenesis.

Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. While the histopathology of the different disease stages is well characterized, the cause underlying the progression, from the early drusen stage to the advanced macular degeneration stage that leads to blindness, remains unknown. Here, we show that photoreceptors (PRs) of diseased individuals display increased expression of two key glycolytic genes, suggestive of a glucose shortage during disease. Mimicking aspects of this metabolic profile in PRs of wild-type mice by activation of the mammalian target of rapamycin complex 1 (mTORC1) caused early drusen-like pathologies, as well as advanced AMD-like pathologies. Mice with activated mTORC1 in PRs also displayed other early disease features, such as a delay in photoreceptor outer segment (POS) clearance and accumulation of lipofuscin in the retinal-pigmented epithelium (RPE) and of lipoproteins at the Bruch’s membrane (BrM), as well as changes in complement accumulation. Interestingly, formation of drusen-like deposits was dependent on activation of mTORC1 in cones. Both major types of advanced AMD pathologies, including geographic atrophy (GA) and neovascular pathologies, were also seen. Finally, activated mTORC1 in PRs resulted in a threefold reduction in di-docosahexaenoic acid (DHA)–containing phospholipid species. Feeding mice a DHA-enriched diet alleviated most pathologies. The data recapitulate many aspects of the human disease, suggesting that metabolic adaptations in photoreceptors could contribute to disease progression in AMD. Identifying the changes downstream of mTORC1 that lead to advanced pathologies in mouse might present new opportunities to study the role of PRs in AMD pathogenesis.