Complement Component C3 Plays a Critical Role in Protecting the Aging Retina in a Murine Model of Age-Related Macular Degeneration

Complement component C3 is the central complement component and a key inflammatory protein activated in age-related macular degeneration (AMD). AMD is associated with genetic variation in complement proteins that results in enhanced activation of C3 through the complement alternative pathway. These include complement factor H (CFH), a negative regulator of C3 activation. Both C3 inhibition and/or CFH augmentation are potential therapeutic strategies in AMD. Herein, we examined retinal integrity in aged (12 months) mice deficient in both factors H and C3 (CFH−/−.C3−/−), CFH alone (CFH−/−), or C3 alone (C3−/−), and wild-type mice (C57BL/6). Retinal function was assessed by electroretinography, and retinal morphological features were analyzed at light and electron microscope levels. Retinas were also stained for amyloid β (Aβ) deposition, inflammation, and macrophage accumulation. Contrary to expectation, electroretinograms of CFH−/−.C3−/− mice displayed more severely reduced responses than those of other mice. All mutant strains showed significant photoreceptor loss and thickening of Bruch's membrane compared with wild-type C57BL/6, but these changes were greater in CFH−/−.C3−/− mice. CFH−/−.C3−/− mice had significantly more Aβ on Bruch's membrane, fewer macrophages, and high levels of retinal inflammation than the other groups. Our data show that both uncontrolled C3 activation (CFH−/−) and complete absence of C3 (CFH−/−.C3−/− and C3−/−) negatively affect aged retinas. These findings suggest that strategies that inhibit C3 in AMD may be deleterious.