Complement and Inflammatory Factors in AD Pathogenesis

描述(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有的神经病理变化有关，包括突触和神经元丢失、神经纤维缠结和由β-淀粉样蛋白(Abeta)沉积组成的细胞外老年斑。补体蛋白、急性期蛋白和反应性胶质细胞与AD脑内老年斑的相关性表明，炎症过程可能在AD疾病中发挥作用，补体激活可能有助于这些炎症事件的启动。然而，补体激活在AD病理和痴呆中的实际作用尚未确定。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起着有害的作用。过度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显示，与具有正常功能的经典补体途径的动物相比，炎症较少，关键神经元结构的丢失也较少。由于已知纤维Abeta和C1q之间对这种激活至关重要的相互作用部位，开发潜在的治疗方法来阻断导致补体激活的淀粉样蛋白与C1q的相互作用应该是可行的。这里描述的研究计划专注于生成更接近和关键地模拟人类疾病的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功能，并比较与年龄相关的对大脑病理和行为的影响。这些新的模型将测试补体激活促进AD病理和认知功能障碍进展的假说，当纤维Aβ存在时，将对在更接近人类情况的体内环境中测试AD的候选治疗方法有价值。

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.