INVESTIGATION OF COMPLEMENT INDUCED NEUROTOXIC AND NEUROPROTECTIVE PATHWAYS

项目4： 补体蛋白Clq和C5a诱导的神经保护和神经炎症 补体系统是先天免疫系统的一个组成部分，其功能是识别偏差 从正常(如感染或组织损伤)中恢复，并启动保护和启动修复的响应 受伤区域的情况。然而，如果没有适当的监管，就会导致组织损伤。之前的观察表明， 淀粉样蛋白对阿尔茨海默病晚期补体激活的不利影响 含有纤维的斑块聚集，从而激活补体，形成淀粉样肽AB。 CLQ是补体激活途径的识别成分，与纤维淀粉样蛋白和 激活这条通路。补体激活的一个下游产物是C5a，它被认为可以增强 通过与特定受体结合而引起的炎症。在这项提案中，一种C5a受体拮抗剂已经证明 在其他模型中有效地限制补体介导的炎症，正在作为潜在的靶向进行测试 治疗阿尔茨海默病小鼠模型。这一抑制点将使补体级联的其余部分 完好无损，从而允许补体的潜在有益作用，如增强异常清除 (淀粉样蛋白)沉积(通过C3b)、凋亡细胞和/或细胞碎片(通过Clq和C3b)。然而，它也是 越来越多的证据表明，C5a既有激活的受体，也有调节/诱骗受体表达 大脑，因此我们建议确定这些受体的表达平衡是否决定了 阿尔茨海默病大脑中的炎症。此外，已知作为应答而合成和分泌的Clq 对损伤，最近被证明下调外周巨噬细胞中的促炎细胞因子和 为体外培养的神经元提供生存信号。使用几种体外方法，这些神经保护的基础 事件将被定义。这些拟议研究的结果应提供可靠的数据，说明 补体诱导的炎症事件在AD和可能的其他神经退行性疾病中的作用 上了年纪的人。这里确定的有害过程的治疗抑制剂以及试剂或 促进诱导的神经保护功能的治疗随后可以被设计成减缓 这种老年人的普遍疾病的进展。

Project 4: Neuroprotection and neuroinflammation induced by the complement proteins Clq and C5a The complement system is a component of the innate immune system whose function is to recognize deviations from the norm (such as an infection or tissue injury) and to initiate a response that will protect and initiate repair of the injured area. If not properly regulated however, tissue damage results. Previous observations suggest a detrimental effect of the activation of the complement cascade at a late stage of Alzheimer's disease when amyloid plaques containing the fibrillar, and thus complement activating, form of the amyloid peptide, AB, accumulate. Clq, the recognition component of one pathway of complement activation, binds to fibrillar amyloid and activates the pathway. One downstream product of complement activation is C5a which is known to enhance inflammation by binding to specific receptors. In this proposal, a C5a receptor antagonist which has proven effective in limiting complement mediated inflammation in other models, is being tested as a potential targeted therapy in AD mouse models. This point of inhibition would leave the remainder of the complement cascade intact, thereby permitting potentially beneficial effects of complement, such as enhanced clearance of abnormal (amyloid) deposits (by C3b), apoptotic cells and/or cellular debris (by Clq and C3b). However, it is also becoming increasingly evident that there are both activating and modulating/decoy receptors for C5a expressed in brain, and thus we propose to determine whether the balance of expression of these receptors dictates the degree of inflammation in the AD brain. In addition, Clq, which is known to be synthesized and secreted as a response to injury, has recently been shown to down regulate proinflammatory cytokines in peripheral macrophages and to provide survival signals to neurons in vitro. Using several in vitro approaches, the basis for these neuroprotective events will be defined. Results of these proposed studies should provide solid data on the significance of the contribution of complement-induced inflammatory events in AD and likely other neurodegenerative disease in the aging individual. Therapeutic inhibitors of detrimental processes identified here as well as reagents or treatments that promote the neuroprotective functions induced can subsequently be designed to slow the progression of this pervasive disease of the elderly.