APP-BP1, The Cell Cycle, and Alzheimer Disease

APP-BP1、细胞周期和阿尔茨海默病

• 批准号: 7038305
• 负责人: RACHAEL Lee NEVE
• 金额: $ 37.41万
• 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/7038305
• 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）：我们已经确定了与淀粉样蛋白前体蛋白（APP）相互作用的细胞周期蛋白。该蛋白App-BP1在分裂细胞中通过S-M检查点驱动细胞周期。 APP-BP1在神经元中的过表达会导致它们死亡。值得注意的是，神经元中APP的家族性阿尔茨海默氏病（FAD）突变体的表达导致（1）APP-BP1表达的增加，（（2）神经元进入细胞周期的S相中，以及（3）神经元凋亡。此外，相对于对照组，APP-BP1在AD大脑的高风险区域中过表达。 APP-BP1代表了确定细胞周期调节丢失和DNA复制背后的第一个真实“手柄”之一，该机制似乎发生在AD中。我们建议APP与APP-BP1的相互作用对于正常的大脑功能很重要，但是调节两种蛋白质之间的相互作用在AD中会出现问题，从而导致神经元的细胞周期调节衰竭。以下特定目的检验了这一假设： 1。我们将开始定义通过APP-BP1与APP相互作用激活的信号转导途径，其异常激活可能导致神经元进入细胞周期，从而导致细胞凋亡。 2。App-BP1参与了涉及泛素样分子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泛素化途径中App-BP1，NEDD8，ASPP2和其他分子的亚细胞结构，其中与培养和AD Postmortem Brains中的原发性神经元中存在于培养中的原发性神经元中。 3。从完成特定目标1和2获得的数据将表明我们可能希望在验尸大脑中观察到的APP-BP1介导的信号的扰动的具体后果。我们将测试这些预测是否正确。