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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.
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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.
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.
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.
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.
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