Defining the Mechanistic Link between C5aR1 signaling and cognitive loss in Alzheimer's diseases

项目摘要： 据估计，到2050年，美国将有1380万人患有阿尔茨海默病 (AD)如果不开发出改善疾病的治疗方法，每年的成本将超过1.2万亿美元。的相对 AD定义的病理标志物，淀粉样蛋白和过度磷酸化的tau蛋白， 认知功能障碍仍然存在争议，但在AD患者和转基因小鼠中的研究 AD的模型，已经表明淀粉样蛋白是必要的，但不足以发展 认知丧失是AD的关键临床靶点。越来越多的人认为， 脑中神经胶质细胞对淀粉样蛋白的反应，与神经元损伤相关，因此与认知功能相关。 损伤，以及吞噬和清除淀粉样蛋白的能力，以及其他可能有害的 大脑中的物质可能对疾病的发生和发展有重大影响。 补体级联反应是免疫系统的一种强大效应机制， 由纤维状Aβ（fAβ）激活，可增强清除率并诱导炎症。此外，本发明还提供了一种方法， 补体激活依赖性过度突触修剪发生在AD和其他 神经系统疾病我们的数据表明，药理学抑制或基因缺失， C5 aR 1，补体激活促炎片段C5 a的受体，抑制神经突 以及阿尔茨海默病/淀粉样变性小鼠模型中的认知丧失。封锁这一点的影响 C5 a受体与星形胶质细胞活化、炎症和清除相关基因的相互作用 表达，神经元的完整性和突触密度提出了两个目标在这里与最终的 目的是确定C5 aR 1激活和神经元功能丧失之间的机制步骤， 以及C5 aR 1拮抗剂作为人类临床试验的治疗候选物的潜力， 预防认知障碍。在第三个目标中，我们提出使用新生成的小鼠， floxed C5 aR 1，以暂时和细胞特异性地消融受体并评估基因表达， AD小鼠模型中的神经元完整性和功能，以更接近地模拟成人对AD的抑制。 这种受体可能会发生与受体拮抗剂治疗的个体患有或有风险的AD。 选择性调节补体激活产物或其受体可能是最佳策略 用于保留补体成分的神经保护和吞噬功能，以及 全身保护免受病原体裂解，同时抑制诱导的炎性损伤。 重要的是，这种配体-受体系统的阻断在人类中没有显示出不利影响， 这表明可以安全地施用C5 aR 1靶向的AD治疗剂。

Project Summary: By 2050 it is estimated that there will be 13.8 million individuals in the US with Alzheimer's disease (AD), at a cost of over $1.2 trillion per yr, if no disease-modifying therapy is developed. The relative contributions of the AD defining pathological markers, amyloid and hyperphosphorylated tau, to cognitive dysfunction remains controversial, but studies in both AD patients and transgenic mouse models of AD, have shown that amyloid is necessary but not sufficient for the development of cognitive loss which is the key clinical target of AD. There is a growing consensus that it is the response of glial cells in the brain to amyloid that is relevant to neuronal damage and thus cognitive impairment, and that the capacity to phagocytose and clear amyloid and perhaps other deleterious material in the brain may have a substantial influence on the initiation and progression of the disease. The complement cascade, a powerful effector mechanism of the immune system that is directly activated by fibrillar Aβ (fAβ), can both enhance clearance and induce inflammation. In addition, complement activation dependent excessive synapse pruning occurs in models of AD and other neurological disorders. Our data demonstrate that pharmacologic inhibition or genetic deletion of C5aR1, a receptor for the complement activation proinflammatory fragment, C5a, suppresses neurite and cognitive loss in mouse models of Alzheimer's disease/amyloidosis. The effects of blocking this C5a receptor interaction on astrocyte activation, inflammatory and clearance related gene expression, neuronal integrity and synaptic density are proposed in two aims here with the ultimate goal of determining mechanistic steps between activation of C5aR1 and loss of neuronal function, as well as the potential for C5aR1 antagonists as therapeutic candidates for clinical trials in humans to prevent cognitive impairment. In a third aim, we proposed to use a newly generated mouse with a floxed C5aR1, to temporally and cell specifically ablate the receptor and assess gene expression, neuronal integrity and function in an AD mouse model, to more closely mimic the adult inhibition of this receptor that would occur with receptor antagonist treatment of individuals with or at risk for AD. Selective modulation of complement activation products or their receptors may be an optimal strategy for retaining the neuroprotective and phagocytic functions of complement components, as well as systemic protection from pathogens lysis, while dampening induced inflammatory damage. Importantly, blockage of this ligand-receptor system has not shown adverse effects in humans, suggesting that C5aR1-targeted therapeutics for AD may be safely administered.