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- W1760485743 abstract "Complement factor H (CFH) is a major susceptibility gene for age-related macular degeneration (AMD); however, its impact on AMD pathobiology is unresolved. Here, the role of CFH in the development of AMD pathology in vivo was interrogated by analyzing aged Cfh(+/-) and Cfh(-/-) mice fed a high-fat, cholesterol-enriched diet. Strikingly, decreased levels of CFH led to increased sub-retinal pigmented epithelium (sub-RPE) deposit formation, specifically basal laminar deposits, following high-fat diet. Mechanistically, our data show that deposits are due to CFH competition for lipoprotein binding sites in Bruch's membrane. Interestingly and despite sub-RPE deposit formation occurring in both Cfh(+/-) and Cfh(-/-) mice, RPE damage accompanied by loss of vision occurred only in old Cfh(+/-) mice. We demonstrate that such pathology is a function of excess complement activation in Cfh(+/-) mice versus complement deficiency in Cfh(-/-) animals. Due to the CFH-dependent increase in sub-RPE deposit height, we interrogated the potential of CFH as a previously unidentified regulator of Bruch's membrane lipoprotein binding and show, using human Bruch's membrane explants, that CFH removes endogenous human lipoproteins in aged donors. Thus, advanced age, high-fat diet, and decreased CFH induce sub-RPE deposit formation leading to complement activation, which contributes to RPE damage and visual function impairment. This new understanding of the complicated interactions of CFH in AMD-like pathology provides an improved foundation for the development of targeted therapies for AMD." @default.
- W1760485743 created "2016-06-24" @default.
- W1760485743 creator A5039527047 @default.
- W1760485743 creator A5051860617 @default.
- W1760485743 creator A5060494924 @default.
- W1760485743 creator A5063107018 @default.
- W1760485743 date "2015-05-19" @default.
- W1760485743 modified "2023-10-15" @default.
- W1760485743 title "Regulation of age-related macular degeneration-like pathology by complement factor H" @default.
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