Abstract
Purpose:
The relative contribution and potential interactions of known disease risk factors to the pathogenesis of age-related macular degeneration (AMD) remains poorly understood. Aged apolipoprotein E targeted-replacement (APOE4) mice fed a high fat cholesterol-enriched (HFC) diet (APOE4~HFC) have provided a robust model to investigate this question. Considering the association of complement factor H (CFH) polymorphisms with AMD, we interrogated the effects of complement dysregulation on the APOE4~HFC experimental model.
Methods:
Male APOE4; APOE4,Cfh+/-; and APOE4,Cfh-/- mice were aged to 80 weeks. Age-matched mice of each genotype were divided with half continued on a normal mouse diet (ND) and half switched to a HFC diet for 8 weeks immediately before analysis. Electroretinograms (ERGs) and a plasma sample from each mouse were obtained prior to termination. Eyes were isolated for routine histology, electron microscopy, and biochemistry.
Results:
Consistent with previous results (Malek et al. PNAS, 2005), all mice fed HFC, regardless of Cfh genotype, developed basal deposits. Interestingly, APOE4,Cfh+/- mice fed normal diet demonstrated ERG and retinal pigment epithelium (RPE) flat mount changes consistent with RPE stress and photoreceptor dysfunction as well as basal deposits on EM (all exacerbated by HFC diet). These changes recapitulated the phenotype observed in the APOE4 mice fed HFC. Notably, ERG and RPE flat mount changes were not observed in the APOE4,Cfh-/- ND mouse.
Conclusions:
Introducing complement dysregulation via Cfh+/- onto the APOE4 background in aged mice results in AMD-like pathology without the additional requirement of inducing lipid perturbation via HFC diet. These changes do not occur in the complete absence of Cfh, presumably due to excessive alternative pathway activation leading to depletion of complement components and loss of complement system activity. These results underscore the importance of the complement system in the pathophysiology of AMD and provide a new experimental manipulation, in addition to aging and HFC, to cause AMD-like pathology in the APOE4 mouse model.