COMPLEMENT AND INFLAMMATORY FACTORS IN AD PATHOGENESIS

描述(改编自《调查者摘要》)：阿尔茨海默病 (AD)是一种常见的痴呆症或认知能力丧失，与 脑组织变性。这种神经变性的原因是 紧张的调查，作为设计治疗方法的关键一步 使人虚弱且代价高昂的疾病。在各种测试系统中，fiillar β-淀粉样蛋白通过与其直接相互作用表现出神经毒性 但也通过它与小胶质细胞的相互作用(S)和它的能力 激活补体系统。多项研究表明， 反应性小胶质细胞和星形胶质细胞以及补体系统的蛋白质 与AD脑内的衰老斑块有关，提示炎症 由补体系统的激活启动或加剧的可以是一个 导致疾病发生的主要过程是什么？ 认知缺失。补体(C‘)系统是一种强大的效应机制 对免疫系统的影响。然而，组织损伤可能是由于慢性或 这一系统的不受管制的激活。然而，它也正在成为 越来越明显的是，一些补体成分提供了保护 损伤区域的功能。因此，在这个研究项目中，新颖的小鼠模型 将被生成以更接近地模拟人类补体系统来测试 补体在阿尔茨海默病发病机制中起作用的假说 疾病。器官类型培养系统将被用来评估 特异性补体成分修饰淀粉样蛋白诱导的小胶质细胞 神经细胞死亡/变性。此外，潜在的保护作用 将定义这种疾病中的特定补体成分，并 调节这些功能的特定配体-受体相互作用将是 下定决心。这些研究应该提供可靠的数据，说明 AD中的补体激活和炎症事件--这些事件可能是 有针对性地减缓疾病的发展，以及开发相关的 在活体内测试潜在疗法的动物模型。因为补语已经 与其他一些神经退行性疾病有牵连，很可能 研究人员的发现也将与其他疾病相关。

DESCRIPTION (Adapted from the Investigator's Abstract): Alzheimer's disease (AD) is a common dementia or loss of cognitive abilities, which is linked to degeneration of brain tissue. The cause of this neurodegeneration is under intense investigation, as a critical step toward designing therapies for this debilitating and costly disease. In a variety of test systems, fibrillar beta-amyloid displays neurotoxic properties via its direct interaction with neurons but also via its interaction(s) with microglia and its ability to activate the complement system. Multiple studies have demonstrated that reactive microglia and astrocytes and proteins of the complement system are associated with the senile plaques in AD brain, suggesting that inflammation initiated by or exacerbated by activation of the complement system may be one of the major processes involved in the generation of pathology that leads to the cognitive loss. The complement (C') system is a powerful effector mechanism of the immune system. Tissue damage can result however, from chronic or unregulated activation of this system. However, it is also becoming increasingly evident that some complement components provide protective functions in areas of injury. Thus, in this research program novel mouse models will be generated to more closely mimic the human complement system to test the hypothesis that complement plays a role in the pathogenesis of Alzheimer's Disease. Organotypic culture systems will be used to assess the ability of specific complement components to modify amyloid-induced microglia-mediated neuronal cell death/degeneration. In addition, potential protective effects of specific complement components in this disorder will be defined and the specific ligand-receptor interactions that regulate these functions will be determined. These studies should provide solid data on the significance of complement activation and inflammatory events in AD--events which could be targeted to slow the progression of the disease, as well as develop relevant animal models for testing potential therapies in vivo. Since complement has been implicated in a number of other neurodegenerative diseases, it is likely that the investigators' findings will be relevant to other diseases as well.