Age-related macular degeneration (AMD) is a leading cause of visual dysfunction worldwide. It is characterized by the accumulation of extracellular lipid- and protein-containing deposits between the retinal pigment epithelium (RPE) and Bruch's membrane (BrM). These sub-RPE deposits may be focal (drusen) or diffuse and are likely to contribute to disease pathogenesis and progression as documented for extracellular deposits that exemplify other diseases such as Alzheimer's disease. Although the molecular bases of these diseases may be diverse, their pathogenic deposits contain many shared constituents that are attributable, in part, to local inflammation and activation of the complement cascade. The role of complement in AMD pathogenesis is supported by studies identifying complement proteins in drusen and studies implicating variations in the complement factor H (CFH) gene as the strongest genetic factor associated with AMD risk. The associated risk of CFH variants supports the hypothesis that local inflammation and activation of the complement cascade contributes to AMD pathogenesis. The repercussions of the CFH polymorphism on the entire complement system, as it pertains to the maintenance of the health of the eye, are not yet well understood and it seems likely that other triggers, modulators and/or mechanisms act in concert with CFH in disrupting the delicate equilibrium of the complement system. Prominent among these is amyloid beta (A?), a constituent of sub-RPE deposits, which is a known activator of the complement system. We hypothesize that dysregulated complement activity within the RPE/BrM/choroid contributes to RPE damage, sub-RPE deposit formation and AMD progression and A? in this region contributes to complement system dysregulation. In support of this hypothesis, we showed that A? is a viable therapeutic target in the treatment of AMD. For the present study, we have developed three novel mouse models to examine the role of complement in the development of AMD. In the first two models complement activation is suppressed or augmented, respectively, in an established AMD mouse model (Aims 1 and 2) and the third is a new humanized CFH mouse expressing either the normal or AMD risk form of CFH (Aim 3). Each model has a different capacity to accumulate activated complement components in the eye providing us a spectrum of complement deposition and complement-related phenotypes to interrogate the role of CFH in AMD.
Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the sixty- five-and-older population, and the devastating impact of its socioeconomic burden cannot be overstated. Using mouse models that faithfully recapitulate many aspects of human AMD, we have demonstrated that observed ocular defects arise from inflammation, amyloid beta (A?) deposition and complement dysregulation - mechanisms implicated in development of human AMD. Our proposed studies will further clarify the contribution of complement and A? to disease onset and progression. Validation of A? as a novel therapeutic target in AMD could lead to a fundamental paradigm shift in the understanding and treatment of AMD. Moreover, unraveling the impact of excess complement activation versus increased complement inhibition on subRPE deposit formation and RPE damage will help shape the development of complement-targeted therapies that could delay or prevent AMD.
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