Proteolysis of apoE and Alzheimer's pathology

apoE 的蛋白水解和阿尔茨海默病病理学

• 批准号: 6548523
• 负责人: Keith Alan Crutcher
• 金额: $ 37.93万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6548523
• 关键词: Alzheimer's disease; amyloid proteins; apolipoprotein E; brain metabolism; clinical research; genetically modified animals; human tissue; immunocytochemistry; laboratory mouse; neuropathology; neurotoxicology; protein localization; protein protein interaction; proteolysis; receptor expression; tissue /cell culture

DESCRIPTION (provided by applicant): Although abundant new information has recently been collected on the genetic and environmental risk factors associated with Alzheimer's disease, there is still no consensus on the critical pathway leading to neuropathology. The "amyloid hypothesis", which dominates much current research effort, has both strengths and weaknesses. One aspect of the postulated role for amyloid that is particularly contentious is the extent to which it is a direct cause of neuronal degeneration, as opposed to participating in a cascade of events that ultimately leads to neuronal dysfunction and death. Other genetic risk factors for proteins involved in AD include apolipoprotein E (apoE) and there is accumulating evidence that apoE4 may directly contribute to AD neuropathology. In particular, apoE4 has been shown to exhibit neurotoxic effects in vitro. This toxicity may be associated with proteolytic generation of a shortened form of apoE (truncated apoE), which is more abundant in AD brain tissue. In addition, several lines of evidence suggest that a C-terminal fragment of apoE binds to, and co-localizes with, amyloid. The work proposed here will examine the hypothesis that proteolytic fragments of apoE contribute to both neuropathology and amyloid deposition. A combination of immunohistochemical, biochemical, and tissue culture studies will be used to: examine the extent of apoE proteolysis in human brain and apoE transgenic mouse brain; identify the cellular source of apoE and its proteolysis in the CNS; study the role of specific receptors in apoE neurotoxicity; study the effect of C-terminal apoE on ABeta aggregation and activity; and localize apoE fragments at sites of AD pathology. The goal is to pursue evidence in support or against the major hypothesis that proteolysis of apoE contributes to AD pathology.

描述（由申请人提供）：尽管最近已经收集了有关与阿尔茨海默氏病有关的遗传和环境风险因素的大量新信息，但仍未就导致神经病理学的关键途径达成共识。主导当前许多研究工作的“淀粉样假说”具有优势和劣势。淀粉样蛋白特别有争议的假定作用的一个方面是它是神经元变性的直接原因，而不是参加一系列事件，最终导致神经元功能障碍和死亡。 AD参与的蛋白质的其他遗传危险因素包括载脂蛋白E（APOE），并且有积累的证据表明APOE4可能直接有助于AD神经病理学。特别是，已显示APOE4在体外表现出神经毒性作用。这种毒性可能与缩短形式的APOE（截短的APOE）的蛋白水解产生有关，该毒性在AD脑组织中更丰富。此外，几条证据表明，APOE的C末端片段与淀粉样蛋白结合并与淀粉样蛋白共定位。这里提出的工作将研究以下假设：APOE的蛋白水解片段有助于神经病理学和淀粉样蛋白沉积。免疫组织化学，生化和组织培养研究的结合将用于：检查人脑和APOE转基因小鼠脑中APOE蛋白水解的程度；鉴定中枢神经系统中APOE的细胞来源及其蛋白水解；研究特定受体在APOE神经毒性中的作用；研究C末端APOE对ABETA聚集和活性的影响；并将ApoE片段定位在AD病理部位。目的是寻求支持或反对主要假设的证据，即APOE的蛋白水解有助于AD病理学。