title: Regulation of age-related macular degeneration-like pathology by complement factor H.
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.
authors.affiliation: Department of Ophthalmology, Duke Eye Center, Duke University, Durham, NC 27710; Department of Cell Biology, Duke University, Durham, NC 27710;
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Toomey
authors.affiliation: Department of Ophthalmology, Duke Eye Center, Duke University, Durham, NC 27710;
authors.forename: Una
authors.initials: U
authors.lastname: Kelly
authors.affiliation: Department of Ophthalmology, Duke Eye Center, Duke University, Durham, NC 27710; Department of Immunology, Duke University, Durham, NC 27710.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Saban
authors.affiliation: Department of Ophthalmology, Duke Eye Center, Duke University, Durham, NC 27710; Department of Cell Biology, Duke University, Durham, NC 27710; bowes007@duke.edu.
authors.forename: Catherine
authors.initials: C
authors.lastname: Bowes Rickman
mesh_terms: D000818:Animals; D002829:Choroid / Q000378:metabolism / Q000473:pathology; D017242:Complement Factor H / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D059305:Diet, High-Fat; D008268:Macular Degeneration / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000378:metabolism / Q000473:pathology
chemical_list: D017242:Complement Factor H
keywords: age-related macular degeneration; complement; factor H; lipoprotein; retinal pigmented epithelium