April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
Effect Of Excess Complement Inhibition On AMD-like Pathology Using The APOE4/sCrry Transgenic Murine Model: Does Gain-of-function Worsen Retinal Disease?
Author Affiliations & Notes
  • Wenlan Zhang
    Ophthalmology,
    Duke Univ Medical Center, Durham, North Carolina
  • Jin-Dong Ding
    Ophthalmology,
    Duke Univ Medical Center, Durham, North Carolina
  • Una Kelly
    Ophthalmology,
    Duke Univ Medical Center, Durham, North Carolina
  • Stephanie Smith
    Ophthalmology,
    Duke Univ Medical Center, Durham, North Carolina
  • Michael Frank
    Pediatrics,
    Duke Univ Medical Center, Durham, North Carolina
  • Catherine Bowes Rickman
    Ophthalmology,
    Duke Univ Medical Center, Durham, North Carolina
  • Footnotes
    Commercial Relationships  Wenlan Zhang, None; Jin-Dong Ding, None; Una Kelly, None; Stephanie Smith, None; Michael Frank, 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 April 2011, Vol.52, 2294. doi:https://doi.org/
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      Wenlan Zhang, Jin-Dong Ding, Una Kelly, Stephanie Smith, Michael Frank, Catherine Bowes Rickman; Effect Of Excess Complement Inhibition On AMD-like Pathology Using The APOE4/sCrry Transgenic Murine Model: Does Gain-of-function Worsen Retinal Disease?. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2294. 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 inhibition on AMD-like pathology using APOE4/sCrry double transgenic mice. Similar to CFH, soluble complement receptor 1-related protein y (sCrry) is a homologue of human complement receptor 1 and a potent mouse complement inhibitor. 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 sCrry transgenic mice to establish the APOE4/sCrry 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 there were no differences in ERGs between groups, but histological review showed that aged APOE4/sCrry+ animals have slightly less basal deposits and healthier retinal pigmented epithelium (RPE). Moreover, immunohistochemistry found less active C3b fragments in the sub-RPE of these animals when compared to APOE4/sCrry negative (-) littermates lacking sCrry. As expected with complement inhibition, biochemical analyses of plasma confirmed more C3 and less C3a in APOE4/sCrry+ animals on HFC diet compared to APOE4/sCrry- controls on HFC diet.

Conclusions: : These initial findings suggest that the effect of excess complement inhibition, modeling CFH gain-of-function, on an AMD-like murine model is slightly protective. This supports the possibility that dysregulated excess complement activation may play a role in AMD disease pathogenesis and progression.

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