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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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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.
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.
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.
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.
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