Role of Complement in Alzheimer's Disease

补体在阿尔茨海默病中的作用

• 批准号: 7270121
• 负责人: DANIEL SEVLEVER
• 金额: $ 15.13万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7270121
• 关键词: Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Autologous; Automobile Driving; Behavioral; Biological; Blood Vessels; Brain; CD55 Antigens; Cell surface; Cells; Chronic; Complement; Complement 3 Convertase; Complement Activation; Data; Degenerative Disorder; Dementia; Deposition; Disease; Elderly; Epidemiologic Studies; Event; Excision; GPI Membrane Anchors; Gliosis; Goals; Human; Immune System Part; Immune system; Inflammation; Inflammatory; Inflammatory Response; Knockout Mice; Knowledge; Lesion; Longitudinal Studies; Measurement; Mediating; Membrane Proteins; Meningeal; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Pathology; Patients; Peptides; Pharmaceutical Preparations; Plasma; Play; Production; Protein Overexpression; Proteins; Proteolytic Processing; Research Personnel; Risk; Role; Senile Plaques; System; Testing; Tg2576; Therapeutic; Tissues; Transgenic Animals; Transgenic Organisms; abeta accumulation; activation product; behavior test; complement pathway; design; extracellular; genetic regulatory protein; inhibitor/antagonist; mind control; mouse model; neurofibrillary tangle formation; novel therapeutics; peptide A; prevent; programs; protein aggregate; response; theories

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.

描述(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特征之一。AD脑的特征是Aβ多肽在细胞外聚集在淀粉样斑块中，并在神经元内形成缠结。阿尔茨海默病的主要理论假设是Abeta的聚集是导致病理的原因。炎症发生在阿尔茨海默病(AD)大脑的脆弱区域，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发病机制中的作用尚不清楚。由于补体激活产物在淀粉样斑块中的存在，一直认为补体激活参与了AD的病理过程。然而，最近对转基因动物的研究对这一概念提出了挑战。这些研究表明，抑制补体激活会加剧AD的病理，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的沉积。人类和小鼠体内补体激活的一个关键调节因子是衰变加速因子(DAF)。DAF可防止自发的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清除淀粉样斑块。我们将通过研究补体激活在AD病理中的后果来检验这一假设。为了实现这一目标，我们建立了一个AD小鼠模型，其中DAF基因敲除小鼠与Tg2576动物杂交消除了DAF，Tg2576动物是AD的转基因小鼠模型。将对APP+/-/DAF-/-和对照APP+/-/7DAF+/+进行纵向研究，以量化血浆和脑Abeta水平，并评估实质和血管中淀粉样蛋白的沉积、神经病理变化以及炎症标志，如胶质增生和补体激活。这些动物的病理将与行为测试相关。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中的后果。由于某些炎症反应可能是有害的，而另一些可能是有益的，调节补体激活可能是治疗AD的一种方法。