Complement and Inflammatory Factors in AD Pathogenesis

AD 发病机制中的补体和炎症因子

• 批准号: 7230337
• 负责人: Andrea Joan Tenner
• 金额: $ 5.47万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7230337
• 关键词: Alzheimer' s disease; amyloid proteins; central nervous system; complement; complement pathway; disease /disorder model; gene deletion mutation; gene expression; genetically modified animals; glia; hemolysis; inflammation; laboratory mouse; laboratory rabbit; long term potentiation; model design /development; neural degeneration; neuropathology; pathologic process; tissue /cell culture

DESCRIPTION (provided by applicant): Alzheimer's Disease (AD) is a neurodegenerative disorder associated with the loss of cognitive function and the presence of characteristic neuropathological changes that include synaptic and neuronal loss, neurofibrillary tangles and extracellular senile plaques composed of beta-amyloid (Abeta) protein deposits. The association of complement proteins, as well as acute phase proteins and reactive glia, with senile plaques in AD brain suggests that inflammatory processes may play a role in this disease, and that complement activation may contribute to the initiation of these inflammatory events. However, the actual in vivo contribution of complement activation to pathology and dementia in AD has not yet been determined. Our recently completed study provides compelling evidence for a detrimental role for C1q (the initiation component of the classical complement pathway) in the progression of pathology in murine models of Alzheimer's Disease. Animals overexpressing the amyloid precursor protein but lacking the ability to activate the classical complement pathway showed less inflammation and less loss of critical neuronal structures than those with a functioning classical complement pathway. Since sites of interaction between fibrillar Abeta and C1q critical for this activation are known, the development of potential therapies that would block the amyloid interaction with C1q that leads to complement activation should be feasible. The research program described here focuses on the generation of animal models of AD that more closely and critically mimic the human disease. The models will be genetically manipulated to either eliminate or enhance specific features of the complement system, and the age-related consequences on brain pathology and behavior compared. These novel models will test the hypothesis that complement activation promotes the progression of pathology and cognitive dysfunction in AD at a stage when fibrillar Abeta is present, and will be valuable for testing candidate therapies for AD in an in vivo context that more closely mimics the human condition.

描述（由申请人提供）：阿尔茨海默病（AD）是一种与认知功能丧失和存在特征性神经病理学变化相关的神经退行性疾病，所述特征性神经病理学变化包括突触和神经元丧失、神经元缠结和由β-淀粉样蛋白（Abeta）沉积物组成的细胞外老年斑。补体蛋白以及急性期蛋白和反应性神经胶质与AD脑中的老年斑的关联表明炎症过程可能在这种疾病中起作用，并且补体激活可能有助于这些炎症事件的启动。然而，补体激活对AD病理和痴呆的实际体内贡献尚未确定。我们最近完成的研究提供了令人信服的证据，C1 q（经典补体途径的起始组分）在阿尔茨海默病小鼠模型的病理进展中起着有害作用。过表达淀粉样前体蛋白但缺乏激活经典补体途径能力的动物比具有功能性经典补体途径的动物表现出更少的炎症和更少的关键神经元结构损失。由于纤维状Abeta和C1 q之间的相互作用位点对于这种激活至关重要，因此开发可能阻断淀粉样蛋白与C1 q相互作用导致补体激活的潜在疗法应该是可行的。这里描述的研究计划集中在AD动物模型的产生，更密切和更严格地模仿人类疾病。这些模型将被遗传操纵，以消除或增强补体系统的特定功能，并比较与年龄相关的脑病理学和行为后果。这些新模型将检验补体激活在纤维状Abeta存在的阶段促进AD中病理学和认知功能障碍进展的假设，并且对于在更接近模拟人类状况的体内背景下测试AD的候选疗法将是有价值的。