INVESTIGATION OF COMPLEMENT INDUCED NEUROTOXIC AND NEUROPROTECTIVE PATHWAYS

项目四： 补体蛋白Clq和C5 a诱导的神经保护和神经炎症 补体系统是先天免疫系统的组成部分，其功能是识别偏差 从规范（如感染或组织损伤），并启动反应，将保护和启动修复 受伤的区域。然而，如果不适当地调节，则会导致组织损伤。以前的观察表明， 淀粉样蛋白在阿尔茨海默病晚期激活补体级联反应的有害作用 含有纤维状的、因而是补体激活的淀粉样肽AB形式的斑块积聚。 Clq是补体激活途径之一的识别成分，与纤维状淀粉样蛋白结合， 激活通道补体激活的一种下游产物是C5 a，已知其增强补体激活。 通过与特定受体结合而引起炎症。在该提议中，C5 a受体拮抗剂已被证明 在其他模型中有效限制补体介导的炎症，正被测试为潜在的靶向 治疗AD小鼠模型。这个抑制点将留下补体级联的剩余部分 完整的，从而允许补体的潜在有益作用，如增强的异常补体的清除。 （淀粉样蛋白）沉积物（通过C3 b）、凋亡细胞和/或细胞碎片（通过Clq和C3 b）。但也 越来越明显的是，存在C5 a的激活和调节/诱饵受体，其在细胞中表达。 因此，我们建议确定这些受体的表达平衡是否决定了大脑中的程度。 AD大脑中的炎症此外，已知Clq作为应答被合成和分泌， 损伤，最近已显示下调外周巨噬细胞中的促炎细胞因子， 为体外神经元提供存活信号。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关于 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 衰老的个体此处确定的有害过程的治疗抑制剂以及试剂或 随后可以设计促进诱导的神经保护功能的治疗，以减缓神经保护功能。 这是老年人普遍性疾病的进展。

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.