Role of Complement in Alzheimer's Disease

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，其中蛋白质聚集是该疾病的病理标志之一。阿尔茨海默病大脑的特征是淀粉样斑块中β肽的细胞外积累和神经元内缠结的形成。阿尔茨海默病的主要理论假设β的聚集是导致病理的原因。炎症发生在AD大脑的脆弱区域，一些观察到的炎症事件可能与Aa激活补体有关。补体途径是先天免疫系统的一个分支，其在AD病理中的作用尚不清楚。由于淀粉样斑块中存在补体活化产物，因此一直认为补体活化有助于AD病理。然而，这一观念受到了最近转基因动物研究的挑战。这些研究表明，抑制补体激活会加剧AD病理，而增加补体级联的一个关键成分的水平会减少淀粉样蛋白沉积。人类和小鼠体内存在的补体激活的一个关键调节因子是衰变加速因子（DAF）。DAF阻止自发补体激活和补体介导的自体组织损伤。我们的假设是补体有助于淀粉样斑块的清除。我们将通过研究补体激活在AD病理中的后果来验证这一假设。为了实现这一目标，我们通过将DAF敲除小鼠与AD转基因小鼠模型Tg2576杂交，建立了消除DAF的AD小鼠模型。将对APP+/-/DAF-/-和对照APP+/-/7DAF+/+窝鼠进行纵向研究，以量化血浆和脑β水平，并评估实质和血管中的淀粉样蛋白沉积、神经病理变化以及胶质细胞增生和补体活化等炎症标志物。这些动物的病理将与行为测试相关联。补体在阿尔茨海默病中的作用的知识将提供一个更完整的理解疾病病理炎症的后果。由于某些炎症反应可能是有害的，而另一些可能是有益的，因此调节补体激活可能是治疗AD的一种治疗方法。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is among neuro- degenerative disorders in which protein aggregates are one of the pathological hallmarks of the disease. AD brains are characterized by the extracellular accumulation of Abeta peptide in amyloid plaques and formation of tangles inside neurons. The leading theory in AD postulates that aggregates of Abeta are responsible for driving the pathology. Inflammation occurs in vulnerable regions of the AD brains and some of the observed inflammatory events may be related to the activation of complement by Aa. The complement pathway is a branch of the innate immune system, whose role on AD pathology is poorly understood. Because of the presence of complement activation products in amyloid plaques, it has been assumed that complement activation contributes to AD pathology. However, this notion has been challenged by recent studies with transgenic animals. These studies showed that inhibition of complement activation exacerbates AD pathology, while increasing the levels of a key component of the complement cascade reduces amyloid deposits. One key regulator of complement activation present in humans and mice is decay accelerating factor (DAF). DAF prevents spontaneous complement activation and complement-mediated autologous tissue damage. Our hypothesis is that complement contributes to the removal of amyloid plaques. We will test this hypothesis by studying the consequences of complement activation in AD pathology. To achieve this goal, we have generated an AD mouse model in which DAF was eliminated by crossing DAF knockout mice with Tg2576 animals, a transgenic mouse model of AD. Longitudinal studies of APP+/-/DAF-/- and control APP+/-/7DAF+/+ littermates will be performed to quantify plasma and brain Abeta levels and to evaluate amyloid deposition in parenchyma and blood vessels, neuropathological changes, and markers of inflammation such as gliosis and complement activation. The pathology in these animals will be correlated with behavioral tests. Knowledge of the role of complement in AD will provide a more complete understanding of the consequences of inflammation in the disease pathology. Since certain inflammation responses can be detrimental while others can be beneficial, modulation of complement activation may be one therapeutic approach for the treatment of AD.