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Proc Natl Acad Sci U S A. 2015 Jun 9;112(23):E3040-9. doi: 10.1073/pnas.1424391112. Epub 2015 May 19.

Regulation of age-related macular degeneration-like pathology by complement factor H.

Author information

1
Department of Ophthalmology, Duke Eye Center, Duke University, Durham, NC 27710; Department of Cell Biology, Duke University, Durham, NC 27710;
2
Department of Ophthalmology, Duke Eye Center, Duke University, Durham, NC 27710;
3
Department of Ophthalmology, Duke Eye Center, Duke University, Durham, NC 27710; Department of Immunology, Duke University, Durham, NC 27710.
4
Department of Ophthalmology, Duke Eye Center, Duke University, Durham, NC 27710; Department of Cell Biology, Duke University, Durham, NC 27710; bowes007@duke.edu.

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.

KEYWORDS:

age-related macular degeneration; complement; factor H; lipoprotein; retinal pigmented epithelium

PMID:
25991857
PMCID:
PMC4466717
DOI:
10.1073/pnas.1424391112
[Indexed for MEDLINE]
Free PMC Article

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