Role of Complement in Alzheimer's Disease

描述（由申请人提供）： 阿尔茨海默病（AD）是神经退行性疾病之一，其中蛋白质聚集体是该疾病的病理标志之一。AD脑的特征在于淀粉样斑块中的Abeta肽的细胞外积累和神经元内缠结的形成。AD的主要理论假定Abeta的聚集体负责驱动病理。炎症发生在AD大脑的脆弱区域，并且观察到的一些炎症事件可能与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病理学中的作用知之甚少。由于淀粉样斑块中存在补体激活产物，因此认为补体激活有助于AD病理学。然而，这一概念受到了最近对转基因动物的研究的挑战。这些研究表明，补体激活的抑制加剧AD病理，而增加补体级联反应的关键组分的水平减少淀粉样蛋白沉积。存在于人类和小鼠中的补体激活的一个关键调节因子是衰变加速因子（decay accelerating factor，简写为ERF）。补体激活可防止自发性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AD病理学中补体激活的后果来验证这一假设。为了实现这一目标，我们已经产生了AD小鼠模型，其中通过将AD基因敲除小鼠与AD的转基因小鼠模型Tg 2576动物杂交来消除AD。将对APP+/-/β-/-和对照APP+/-/β +/+同窝仔进行纵向研究，以定量血浆和脑A β水平，并评价实质和血管中的淀粉样蛋白沉积、神经病理学变化和炎症标志物，如神经胶质增生和补体激活。这些动物的病理学将与行为试验相关。了解补体在AD中的作用将使我们更全面地了解炎症在疾病病理学中的后果。由于某些炎症反应可能是有害的，而其他炎症反应可能是有益的，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.