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

Christopher B. Toomey, Una Kelly, Daniel R. Saban, Catherine Bowes Rickman

Research output: Contribution to journalArticlepeer-review

Abstract

Complement factor H (CFH) is a major susceptibility gene for agerelated 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.

Original languageEnglish (US)
Pages (from-to)E3040-E3049
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number23
DOIs
StatePublished - Jun 9 2015
Externally publishedYes

Keywords

  • Age-related macular degeneration
  • Complement
  • Factor H
  • Lipoprotein
  • Retinal pigmented epithelium

ASJC Scopus subject areas

  • General

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