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

Publication ,  Journal Article
Toomey, CB; Kelly, U; Saban, DR; Bowes Rickman, C
Published in: Proc Natl Acad Sci U S A
June 9, 2015

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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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

June 9, 2015

Volume

112

Issue

23

Start / End Page

E3040 / E3049

Location

United States

Related Subject Headings

  • Retinal Pigment Epithelium
  • Monocytes
  • Mice, Transgenic
  • Mice
  • Macular Degeneration
  • Diet, High-Fat
  • Complement Factor H
  • Choroid
  • Animals
 

Citation

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Toomey, C. B., Kelly, U., Saban, D. R., & Bowes Rickman, C. (2015). Regulation of age-related macular degeneration-like pathology by complement factor H. Proc Natl Acad Sci U S A, 112(23), E3040–E3049. https://doi.org/10.1073/pnas.1424391112
Toomey, Christopher B., Una Kelly, Daniel R. Saban, and Catherine Bowes Rickman. “Regulation of age-related macular degeneration-like pathology by complement factor H.Proc Natl Acad Sci U S A 112, no. 23 (June 9, 2015): E3040–49. https://doi.org/10.1073/pnas.1424391112.
Toomey CB, Kelly U, Saban DR, Bowes Rickman C. Regulation of age-related macular degeneration-like pathology by complement factor H. Proc Natl Acad Sci U S A. 2015 Jun 9;112(23):E3040–9.
Toomey, Christopher B., et al. “Regulation of age-related macular degeneration-like pathology by complement factor H.Proc Natl Acad Sci U S A, vol. 112, no. 23, June 2015, pp. E3040–49. Pubmed, doi:10.1073/pnas.1424391112.
Toomey CB, Kelly U, Saban DR, Bowes Rickman C. Regulation of age-related macular degeneration-like pathology by complement factor H. Proc Natl Acad Sci U S A. 2015 Jun 9;112(23):E3040–E3049.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

June 9, 2015

Volume

112

Issue

23

Start / End Page

E3040 / E3049

Location

United States

Related Subject Headings

  • Retinal Pigment Epithelium
  • Monocytes
  • Mice, Transgenic
  • Mice
  • Macular Degeneration
  • Diet, High-Fat
  • Complement Factor H
  • Choroid
  • Animals