Investigating the Mechanisms by which 7-Ketocholesterol Contributes to Age-Related Macular Degeneration
Here researchers construct a model to try to identify the precise mechanisms by which the buildup of 7-ketocholesterol (7KCh) in cells with age contributes to the development of macular degeneration. 7-ketocholesterol is one of the forms of metabolic waste that our biochemistry struggles to break down, and its accumulation is associated with a range of conditions from macular degeneration to atherosclerosis - it is one of the causes of aging. The scientific staff of the SENS Research Foundation have been working for years on mining the bacterial world for enzymes that can break down 7-ketocholesterol and other hardy waste compounds that contribute to age-related disease. Progress is slow, but candidates have been identified: a company was recently launched based on that work. Safely breaking down and removing waste compounds like 7-ketocholesterol is a necessary part of any future toolkit of rejuvenation therapies capable of holding back the aging process and preventing age-related disease, so progress on this front is to be encouraged.
The progression of age-related macular degeneration (AMD) involves a transition from an early or intermediate stage, in which extracellular deposits called drusen accumulate on the inner surface of Bruch's membrane, to an advanced stage featuring photoreceptor and retinal pigment epithelium (RPE) atrophy and/or choroidal neovascularization (CNV), which lead to central vision loss. While the mechanisms driving this progression are unknown, they have been linked to lipid transport and metabolism in the retina as variants in genes involved in these processes have been found to confer increased risk of AMD progression in several genome-wide association studies. Additionally, histological studies have demonstrated the accumulation of phospholipids and cholesterol in the Bruch's membrane (BrM)-retinal pigment epithelium (RPE) complex, which increases with aging and AMD stage. In the highly oxidative environment of the outer retina, these lipids have been noted to undergo conversion to oxidized species, which exert deleterious changes resembling those found in advanced AMD.One particular species of oxidized lipid is 7-ketocholesterol, an oxysterol commonly found in oxidized low-density lipoprotein (oxLDL) that is associated with cellular toxicity in vascular endothelial and smooth muscle cells as well as in RPE cells. Previous studies have shown that 7KCh is formed by photodamage in the rodent retina via a free radical-mediated mechanism, it localizes to presumed lipoprotein deposits in the non-human primate BrM, choriocapillaris, and RPE layer, and it accumulates with increasing age, particularly in RPE-capped drusen in aged human eyes.
Microglia, the resident immune cell of the retina, are responsible for the local modulation of neuroinflammatory change. Microglia in the young, healthy retina are confined to the inner retina, but with aging, these cells migrate to the subretinal space, where they demonstrate increased activation. This subretinal accumulation of microglia have been associated with disease lesions in AMD histological specimens and in AMD-relevant animal models, and have therefore been hypothesized to drive photoreceptor and RPE degeneration, as well as choroidal neovascularization. The mechanisms driving the migration of aging microglia into the outer retina and their subsequent activation have not been well defined.
In this study, we hypothesize that the age-related deposition of 7KCh is related to subretinal microglial recruitment and activation that in turn contributes to progression to neovascular AMD. We evaluated the specific effects that 7KCh exerts on retinal microglial physiology and explored the notion that 7KCh induces pathogenic microglial changes. Our findings described here indicate that 7KCh acts as a chemoattractant capable of inducing the translocation of retinal microglia to the subretinal space. Once there, uptake of 7KCh by microglia can increase microglial activation, M1 polarization, and expression of angiogenic factors in ways that potentiate AMD progression.