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Shun-Yun Cheng, Joris Cipi, Martin-Paul Agbaga, Shan Ma, Claudio Punzo; Elucidating the role of photoreceptors in AMD pathogenesis. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1220.
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Retinal pigmented epithelium (RPE) cells are the primary cell type affected in age-related macular degeneration (AMD); however, the extrinsic factors contributing to RPE dysfunction remain unclear. Data from macular translocation procedures and from Stargardt’s patients suggest that photoreceptors may partake in RPE pathogenesis. To elucidate the role of photoreceptors in AMD pathogenesis we looked at differences in photoreceptor metabolism between AMD patients and non-diseased individuals and recapitulated those changes in mouse.
To mimic the metabolic pattern seen in photoreceptors of AMD patients we genetically manipulate the mammalian target of rapamycin (mTOR) pathway specifically in photoreceptors of mice by use of the Cre-lox system. Mice where followed over time by funduscopy and histological analyses.
We found that photoreceptors in AMD patients express higher levels of a key aerobic glycolysis gene when compared to photoreceptors of non-diseased individuals. Mimicking this change in mouse photoreceptors resulted in pathologies consistent with pathologies seen in AMD patients. These include sub-RPE and sub-retinal drusen-like deposits, Bruch’s membrane thickening and lipid deposition within the Bruch’s membrane, RPE dysfunction and atrophy including geographic atrophy (in 20% mice) and neovascular pathologies (in 8% of mice). Finally, combining the changes in rods and cones accelerated disease progression.
The data suggests that photoreceptors contribute to AMD pathogenesis, explaining why AMD affects primarily the macular region, as this is the area with the highest photoreceptor density. This finding opens new avenues for therapeutic intervention to treat AMD at earlier stages.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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