Complement and Inflammatory Factors in AD Pathogenesis

描述（由申请人提供）：阿尔茨海默病（AD）是一种神经退行性疾病，与认知功能丧失和特征性神经病理改变相关，包括突触和神经元丧失、神经原纤维缠结和由β -淀粉样蛋白（Abeta）沉积组成的细胞外老年斑。补体蛋白，以及急性期蛋白和反应性胶质细胞与AD大脑老年斑的关联表明，炎症过程可能在该疾病中起作用，补体激活可能有助于这些炎症事件的启动。然而，补体激活对阿尔茨海默病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，证明C1q（经典补体途径的起始成分）在阿尔茨海默病小鼠模型的病理进展中具有有害作用。过度表达淀粉样蛋白前体蛋白但缺乏激活经典补体途径能力的动物比那些具有经典补体途径功能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Abeta和C1q之间的相互作用位点对这种激活至关重要，因此开发潜在的治疗方法来阻止淀粉样蛋白与C1q的相互作用，从而导致补体激活应该是可行的。这里描述的研究计划侧重于生成更接近和严格模仿人类疾病的AD动物模型。这些模型将通过基因操作来消除或增强补体系统的特定特征，并比较与年龄相关的脑病理和行为后果。这些新模型将验证补体激活在纤维β存在的阶段促进AD病理进展和认知功能障碍的假设，并将对在更接近模拟人类状况的体内环境中测试AD候选疗法有价值。

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.