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

Abstract

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.

Amyloid beta deposition and phosphorylated tau accumulation are key features in aged choroidal vessels in the complement factor H knock out model of retinal degeneration

“…Both Aβ and phosphorylated tau were expressed at significantly greater levels in Cfh -/-compared to C57 BL/6 mice. The presence of Aβ and phosphorylated tau in association with choroidal arteries is likely to disrupt outer retinal perfusion, which may impact on retinal function and contribute to photoreceptor loss, which are both significant features in ageing Cfh -/-mice (Hoh Kam et al, 2013).…”

“…Deposition of Aβ is common in disease (Weller et al, 1998;Armstrong, 2012;Mendal et al, 2013), but is also a feature of retinal ageing (Hoh Kam et al, 2010;Hoh Kam et al, 2013). Aβ deposition in brain vasculature causes endothelium dependent vasoconstriction (Thomas et al 1996;Townsend et al 2002;Niwa et al2000).…”

“…3 (Johnson et al, 2002;Lundh von Leithner et al, 2009;Hoh Kam et al, 2010;Hoh Kam et al, 2013). BM is part of the outer retinal blood barrier and deposition here is likely to alter outer retinal perfusion arising from the choroid.…”

“…Cfh -/-mice suffer from features of advanced retinal ageing including elevated inflammation, extra-cellular deposition, reduced photoreceptor numbers and compromised retinal function (Lundh von Leithner et al, 2009;Hoh Kam et al, 2013). They also suffer from premature mitochondrial decline in the retina (Calaza et al, 2015).…”

“…Hence, in our Cfh -/-mice it is likely that there is a restriction in blood flow prior to metabolic transfer across BM and that patterns of permeability are changed as a result of endothelial cell loss. These factors may relate to enhanced photoreceptor loss (Hoh Kam et al 2013) and also to the significant thinning of choroidal tissues found in these mice (Lundh von Leithner et al, 2009). …”