COMPLEMENT AND INFLAMMATORY FACTORS IN AD PATHOGENESIS

描述（改编自研究者摘要）：阿尔茨海默病 (AD)是一种常见的痴呆症或认知能力丧失， 脑组织的退化这种神经退化的原因是 密集的调查，作为设计治疗方法的关键一步， 使人衰弱和昂贵的疾病。在各种测试系统中， β-淀粉样蛋白通过与 神经元，但也通过其与小胶质细胞的相互作用及其能力， 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脑内老年斑相关，表明炎症 由补体系统的激活引发或加剧的疾病可以是一种 病理学产生的主要过程， 认知丧失补体（C '）系统是一种强大的效应机制 免疫系统。然而，组织损伤可由慢性或 不受控制地激活这个系统。然而，它也正在成为 越来越明显是，一些补体成分提供保护性 在受伤领域发挥作用。因此，在这项研究计划中， 将产生更接近模仿人类补体系统，以测试 补体在阿尔茨海默病发病机制中起作用的假说 疾病器官型培养系统将用于评估 特异性补体成分修饰淀粉样蛋白诱导的小胶质细胞介导的 神经元细胞死亡/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， 调节这些功能的特定配体-受体相互作用将被 测定这些研究应该提供可靠的数据， 补体激活和炎症事件--这些事件可能 有针对性地减缓疾病的进展，以及发展相关的 用于测试体内潜在疗法的动物模型。由于补有 与许多其他神经退行性疾病有关， 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.