APP-BP1, The Cell Cycle, and Alzheimer Disease

APP-BP1、细胞周期和阿尔茨海默病

• 批准号: 6610749
• 负责人: RACHAEL Lee NEVE
• 金额: $ 38.32万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-15 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6610749
• 关键词: Alzheimer's disease; DNA binding protein; amyloid proteins; apoptosis; biological signal transduction; cell cycle; cell cycle proteins; confocal scanning microscopy; human tissue; immunofluorescence technique; laboratory rat; neurons; protein protein interaction; tissue /cell culture; ubiquitin

DESCRIPTION (provided by applicant): We have identified a cell cycle protein that interacts with the intracellular domain of the amyloid precursor protein (APP). This protein, APP-BP1, drives the cell cycle through the S-M checkpoint in dividing cells. Overexpression of APP-BP1 in neurons causes them to die. Notably, expression of familial Alzheimer disease (FAD) mutants of APP in neurons results in (1) an increase in expression of APP-BP1, (2) entry of the neurons into the S phase of the cell cycle, and (3) neuronal apoptosis. Furthermore, APP-BP1 is overexpressed in at-risk regions of AD brain relative to controls. APP-BP1 represents one of the first real "handles" for determining the mechanism behind the loss of cell cycle regulation and DNA replication that appears to occur in AD. We propose that the interaction of APP with APP-BP1 is important for normal brain function, but that the regulation of the interaction between the two proteins goes awry in AD, resulting in cell cycle regulatory failure in neurons. The following specific aims test this hypothesis: 1. We will begin to define the signal transduction pathway that is activated by interaction of APP-BP1 with APP, and whose abnormal activation may cause entry of neurons into the cell cycle, resulting in apoptosis. 2. APP-BP1 participates in a novel ubiquitination-related pathway involving the ubiquitin-like molecule NEDD8. We will use immunofluorescence and confocal microscopy to identify the subcellular structures in which APP-BP1, NEDD8, ASPP2, and other molecules in the ubiquitinylation-related pathway reside, in primary neurons in culture and in control and AD postmortem brains. 3. The data obtained from accomplishment of specific aims 1 and 2 will suggest specific consequences of perturbations of APP-BP1-mediated signaling that we might expect to observe in postmortem AD brain. We will test whether these predictions are correct.

描述（由申请人提供）：我们已经鉴定了一种与淀粉样前体蛋白（APP）的胞内结构域相互作用的细胞周期蛋白。这种蛋白质 APP-BP1 通过分裂细胞中的 S-M 检查点驱动细胞周期。神经元中 APP-BP1 的过度表达会导致神经元死亡。值得注意的是，神经元中 APP 的家族性阿尔茨海默病 (FAD) 突变体的表达导致 (1) APP-BP1 表达增加，(2) 神经元进入细胞周期的 S 期，以及 (3) 神经元凋亡。此外，相对于对照组，APP-BP1 在 AD 大脑的危险区域过度表达。 APP-BP1 代表了第一个真正的“手柄”，用于确定 AD 中出现的细胞周期调节和 DNA 复制丧失背后的机制。我们认为 APP 与 APP-BP1 的相互作用对于正常的大脑功能很重要，但在 AD 中两种蛋白质之间相互作用的调节出现了问题，导致神经元的细胞周期调节失败。以下具体目标检验该假设： 1. 我们将开始定义APP-BP1与APP相互作用所激活的信号转导通路，其异常激活可能导致神经元进入细胞周期，导致细胞凋亡。 2. APP-BP1 参与涉及泛素样分子 NEDD8 的新型泛素化相关途径。我们将使用免疫荧光和共聚焦显微镜来识别培养物中的原代神经元以及对照和 AD 死后大脑中 APP-BP1、NEDD8、ASPP2 和泛素化相关途径中的其他分子所驻留的亚细胞结构。 3. 从实现特定目标 1 和 2 获得的数据将表明 APP-BP1 介导的信号传导扰动的特定后果，我们可能期望在死后 AD 大脑中观察到这些后果。我们将测试这些预测是否正确。