Age-related macular degeneration (AMD) is a late-onset, progressive, neurodegenerative retinal disease with devastating impact on the elderly. The pathogenesis of AMD is clearly multifactorial in which advanced age is the strongest known risk factor, but other factors including gender, ethnicity, smoking, hypercholesterolemia, and diet play important roles. AMD is also influenced by specific AMD-susceptibility genes. One of these is the APOE gene coding for the apolipoprotein E protein a key regulator of cholesterol and lipoprotein metabolism. Polymorphisms in another gene, CFH, coding for complement factor H and factor H-like protein 1, is a major contributor to AMD susceptibility, supporting an association of the complement system and inflammation with AMD. Recently, we established a murine model that recapitulates ocular pathologies of AMD by applying three physiologically relevant risk factors: specific APOE genotype, advanced age and high fat/cholesterol-rich diet. These mice develop sub-retinal pigment epithelium (RPE) deposits, RPE atrophy and choroidal neovascularization. Importantly, these changes require the presence of all three risk factors. Our analyses suggest this pathogenesis arises from lipid transport dysregulation, inflammation and amyloid ? (A?) peptide deposition, strikingly similar to the pathogenesis of Alzheimer's disease. In Alzheimer's disease, immunotherapy targeting A? has been shown to reduce the number of amyloid deposits and enhance cognition in humans and animal models. Therefore we propose that A? also contributes to AMD pathogenesis and may be an attractive therapeutic target in AMD. Indeed, the results of our pilot prevention studies indicate that antibody targeting of A? in our AMD mouse model reduces amyloid burden and ameliorates the disease phenotype. Furthermore, the overlap of inflammation and amyloid in both diseases suggests that components of the innate immune response (namely, complement) interact directly with A? in AMD. In addition, consistent with the Alzheimer's disease literature - that there is an interaction between A? and complement activation - we propose that there is a co-dependence of A? and complement in AMD pathogenesis and progression. Specifically, in this application we will test the hypothesis that A? peptide deposition activates complement in AMD, and that A? is a valid therapeutic target in AMD.
Aim 1 : To test the hypothesis that increased amyloid burden and complement dysregulation exacerbates AMD-like pathologies in a mouse model of AMD.
Aim 2 : To test the corollary hypothesis that decreased amyloid ameliorates AMD-like pathologies in a mouse model of AMD.
Aim 3 : To test the hypothesis that the genetic association of CFH variants conferring risk of AMD is correlates with the strength of to the molecular interaction of complement factor H, complement component 3b and amyloid ?.
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. Recently, we have established a mouse model of the disease that faithfully recapitulates the pathology of human AMD and have demonstrated that the observed ocular defects arise from lipid transport dysregulation, inflammation and amyloid beta (A?) peptide deposition - mechanisms strikingly similar to those proposed as the etiology of Alzheimer's disease. Our proposed studies will test the A? peptide hypothesis of AMD and evaluate the contribution of A? and dysregulation of the inflammatory mediator, complement, to AMD pathogenesis. Validation of A? as a novel therapeutic target in AMD could lead to a fundamental paradigm shift in the understanding and treatment of AMD.
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