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

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.

MTOR‐initiated metabolic switch and degeneration in the retinal pigment epithelium

“…65 A recent study by Cheng et al reported that the deletion of Tsc1 in photoreceptor cells caused retinal and RPE degeneration, accumulation of lipids and lipoproteins, and retinal vascular lesions in mice at an advanced age. 66 AMD is a common disease involving the degeneration of the outer retina, RPE and choroid. 19 Other than the genetic predispositions, RPE cells have intrinsic properties rendering them more vulnerable to age-dependent degeneration.…”

Progressive Photoreceptor Dysfunction and Age-Related Macular Degeneration-Like Features in rp1l1 Mutant Zebrafish

“…Small animal models of drusen and drusen-like deposits have been sought after for decades. There are some mouse models that develop drusen similar to what is observed in humans in terms of composition and location [ 42 , 43 , 44 , 45 ]. Recently, a mouse model with photoreceptor dysfunction and subretinal drusenoid deposits due to impaired cholesterol metabolism was reported [ 46 ].…”

“…Additionally, white lesions observed on funduscopy appeared drusen-like but were actually indicators of retinal atrophy or intra-retinal lesions, not lipid accumulation [ 48 , 49 , 50 ]. Of note, mouse models that develop drusen or subretinal drusenoid deposits are often complex double mutants or have mutations in genes not associated with AMD [ 42 , 43 , 44 , 45 , 46 ]. Our zebrafish model of photoreceptor disease in a cone-rich retina has mutations in a gene known to cause photoreceptor degeneration in humans.…”

Power to see—Drivers of aerobic glycolysis in the mammalian retina: A review

“…There are now growing bodies of evidence to suggest that altered glucose metabolism contributes to the pathology of age-related macular degeneration and retinitis pigmentosa. [18][19][20][21][22][23] It should be recognized that oxygen is rapidly consumed by the retina, and is essential for ATP production and retinal function regardless of glucose availability. 11,16 In vascular mammalian retinas, such as those of the cat, pig and rat, microelectrode measurements of oxygen tension throughout the retina have demonstrated that the photoreceptors are well-oxygenated by the choroid, and that the inner layers are oxygenated by the retinal vasculature.…”

“…Altogether, these data demonstrate that glycolysis is essential for retinal function and survival, and why disruption of retinal glucose metabolism is an expected cause of visual disease. There are now growing bodies of evidence to suggest that altered glucose metabolism contributes to the pathology of age‐related macular degeneration and retinitis pigmentosa 18‐23 …”