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Updated: Apr 12, 2026
Enrichment of Bruch's Membrane from Human Donor Eyes
Published on: November 15, 2015
Regulation of age-related macular degeneration-like pathology by complement factor H
Christopher B Toomey1, Una Kelly2, Daniel R Saban3
1Department of Ophthalmology, Duke Eye Center, Duke University, Durham, NC 27710; Department of Cell Biology, Duke University, Durham, NC 27710;
Insights
Reduced complement factor H (CFH) levels worsen age-related macular degeneration (AMD) pathology by increasing deposits and complement activation. This study clarifies CFH
Area of Science:
- Ophthalmology
- Immunology
- Genetics
Background:
- Complement factor H (CFH) is a key genetic risk factor for age-related macular degeneration (AMD).
- The precise role of CFH in AMD pathogenesis remains incompletely understood.
- AMD is a leading cause of vision loss in older adults.
Purpose of the Study:
- To investigate the in vivo role of CFH in the development of AMD-like pathology.
- To elucidate the mechanisms by which reduced CFH levels contribute to AMD.
- To explore CFH's potential as a regulator of lipoprotein binding in Bruch's membrane.
Main Methods:
- Analysis of aged mice with partial (Cf h(+/-)) and complete (Cf h(-/-)) CFH deficiency on a high-fat diet.
- Assessment of sub-retinal pigmented epithelium (sub-RPE) deposit formation and RPE damage.
- Investigation of complement activation pathways.
- Studies using human Bruch's membrane explants to assess CFH's lipoprotein binding activity.
Main Results:
- Decreased CFH levels led to increased sub-RPE basal laminar deposits in mice fed a high-fat diet.
- These deposits result from CFH competition for lipoprotein binding sites in Bruch's membrane.
- RPE damage and vision loss occurred only in partially deficient mice (Cf h(+/-)) due to excess complement activation, unlike complement-deficient mice (Cf h(-/-)).
- CFH was shown to remove endogenous lipoproteins from human Bruch's membrane explants.
Conclusions:
- A combination of advanced age, high-fat diet, and reduced CFH induces sub-RPE deposit formation.
- This process triggers complement activation, leading to RPE damage and impaired visual function.
- Findings provide a mechanistic understanding of CFH's role in AMD and suggest therapeutic targets.
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.
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