March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Effect of Excess Complement Activation on AMD-like Pathology in the APOE4/cfh Knockout Transgenic Murine Model: Does Loss-of-function Exacerbate Retinal Disease?
Author Affiliations & Notes
  • Joseph G. Christenbury
    Ophthalmology,
    Duke University Medical Center, Durham, North Carolina
  • Jin-Dong Ding
    Ophthalmology,
    Duke University Medical Center, Durham, North Carolina
  • Una Kelly
    Ophthalmology,
    Duke University Medical Center, Durham, North Carolina
  • Marybeth Groelle
    Ophthalmology,
    Duke University Medical Center, Durham, North Carolina
  • Catherine Bowes Rickman
    Ophthalmology and Cell Biology,
    Duke University Medical Center, Durham, North Carolina
  • Footnotes
    Commercial Relationships  Joseph G. Christenbury, None; Jin-Dong Ding, None; Una Kelly, None; Marybeth Groelle, None; Catherine Bowes Rickman, None
  • Footnotes
    Support  NIH Grant EY019038, P30 EY005722, Research to Prevent Blindness, Inc., Ruth and Milton Steinbach Fund, Macular Vision Research Foundation
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 1641. doi:https://doi.org/
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      Joseph G. Christenbury, Jin-Dong Ding, Una Kelly, Marybeth Groelle, Catherine Bowes Rickman; Effect of Excess Complement Activation on AMD-like Pathology in the APOE4/cfh Knockout Transgenic Murine Model: Does Loss-of-function Exacerbate Retinal Disease?. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1641. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : There is strong evidence implicating local inflammation and complement dysregulation in AMD. Complement factor H (CFH) polymorphisms are the strongest genetic risk factor, but little is known about how risk is conferred. Since CFH is a known complement alternative pathway inhibitor, we studied the in vivo effects of excess complement activation on AMD-like pathology using APOE/cfh-/- double transgenic mice. Here, we analyzed whether this complement system manipulation worsened or ameliorated the APOE4 AMD-like phenotype.

Methods: : The APOE4 murine model manifests an AMD-like phenotype in animals aged over 65 weeks and fed a high fat cholesterol-enriched (HFC) diet. Homozygous APOE4/APOE4 mice were crossed with cfh-/- transgenic mice to establish the APOE4/cfh-/- double transgenic line. Experimental animals were aged and fed a HFC diet. We used electroretinograms (ERGs), histology, immunohistochemistry, Western blots, C3a ELISA and C3 hemolysis assays to study the impact of complement cascade dysregulation.

Results: : Preliminary results show that the ERGs of aged APOE4/cfh-/- mice on normal diet and on HFC display impaired visual function compared to APOE4 controls on normal diet. Histological review reveals that aged APOE4/cfh-/- mice on and off HFC diet display a similar number of basal deposits and degree of vacuolization as compared to APOE4 controls. However, RPE was more damaged in APOE4/cfh-/- mice than APOE4 controls, especially in mice fed a HFC diet.Analysis of complement components in plasma confirmed that there was less C3 and more C3b in APOE4/cfh-/- animals compared to APOE4 and APOE4/sCrry (which produces excess complement inhibition) controls.

Conclusions: : These initial findings suggest that the effect of excess complement activation, modeling CFH loss-of-function, on an AMD-like murine model damages visual function. This supports the central importance of complement factor H in the pathophysiology of AMD and use of this animal model to study complement dysregulation in AMD.

Keywords: age-related macular degeneration • immunomodulation/immunoregulation • transgenics/knock-outs 
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