The APOE TR Mouse: A Model for Elucidating Pathogenic Mechanisms of AMD

描述(申请人提供)：年龄相关性黄斑变性(AMD)是一种晚发、进行性、神经退行性视网膜疾病，对老年人的影响是毁灭性的。AMD的发病机制显然是多因素的，其中高龄是已知的最大危险因素，但其他因素包括性别、种族、吸烟、高胆固醇血症和饮食也起着重要作用。AMD还受特定的AMD易感基因的影响。其中之一是编码载脂蛋白E蛋白的载脂蛋白E基因，载脂蛋白E是胆固醇和脂蛋白代谢的关键调节因子。另一个编码补体因子H和因子H样蛋白1的基因CFH的多态是AMD易感性的主要因素，支持补体系统和炎症与AMD的关联。最近，我们通过应用三个生理相关的危险因素：特定的APOE基因、高龄和高脂肪/高胆固醇饮食，建立了一种概括AMD眼部病理变化的小鼠模型。这些小鼠出现视网膜下色素上皮(RPE)沉积、RPE萎缩和脉络膜新生血管。重要的是，这些变化需要所有三个风险因素的存在。我们的分析表明，这一发病机制是由脂质运输失调、炎症和淀粉样蛋白(A)肽沉积引起的，与阿尔茨海默病的发病机制惊人地相似。在阿尔茨海默病中，针对A？的免疫疗法已被证明可以减少淀粉样蛋白沉积的数量，并增强人类和动物模型的认知能力。因此，我们认为A？也参与了AMD的发病，并可能成为治疗AMD的一个有吸引力的靶点。事实上，我们的先导性预防研究的结果表明，在我们的AMD小鼠模型中，A？的抗体靶向减少了淀粉样蛋白的负担，并改善了疾病表型。此外，炎症和淀粉样蛋白在两种疾病中的重叠表明，先天免疫反应的组成部分(即补体)与AMD中的A？直接相互作用。此外，与阿尔茨海默病文献一致的是，A？和补体激活之间存在相互作用-我们提出，在AMD的发病和发展过程中，A？和补体存在相互依赖关系。具体地说，在这项应用中，我们将测试A？肽沉积激活AMD补体的假设，以及A？是AMD的有效治疗靶点的假设。目的1：验证淀粉样蛋白负荷增加和补体失调会加重AMD小鼠模型中AMD样病变的假说。目的2：验证减少淀粉样蛋白可改善AMD小鼠模型中AMD样病变的推论假说。目的：验证CFH变异与AMD发病风险的遗传关联性与补体因子H、补体成分3b和淀粉样蛋白的分子相互作用的强弱有关的假设。公共卫生相关性：老年性黄斑变性(AMD)是65岁及以上人群不可逆转视力丧失的主要原因，其社会经济负担的破坏性影响怎么强调都不为过。最近，我们已经建立了一种疾病的小鼠模型，忠实地概括了人类AMD的病理，并证明了所观察到的眼睛缺陷是由脂质运输失调、炎症和淀粉样β(A)肽沉积引起的--机制与阿尔茨海默病的病因学惊人地相似。我们建议的研究将验证AMD的A？肽假说，并评估A？和炎性介质补体的失调在AMD发病机制中的作用。A？作为AMD新的治疗靶点的确认可能会导致对AMD的理解和治疗的根本范式转变。

DESCRIPTION (provided by applicant): 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 ¿. PUBLIC HEALTH RELEVANCE: 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.