APP-BP1, The Cell Cycle, and Alzheimer Disease

APP-BP1、细胞周期和阿尔茨海默病

• 批准号: 7227074
• 负责人: RACHAEL Lee NEVE
• 金额: $ 36.33万
• 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/7227074
• 关键词: Affect; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Apoptosis; Autopsy; Binding Proteins; Brain; Cell Cycle; Cell Cycle Proteins; Cell Cycle Regulation; Cells; Confocal Microscopy; DNA biosynthesis; Data; Disease; Failure; Functional disorder; Goals; Human; Immunofluorescence Immunologic; Knowledge; Literature; MDM2 gene; Mediating; Mutation; Nerve Degeneration; Neurons; Pathway interactions; Phase; Plant Roots; Play; Protein Binding; Protein Overexpression; Proteins; Regulation; Relative (related person); Risk; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Subcellular structure; Testing; Ubiquitin; Ubiquitination; familial Alzheimer disease; mutant; neuron apoptosis; novel; p53-binding protein

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-BP 1，驱动细胞周期通过分裂细胞中的S-M检查点。APP-BP 1在神经元中的过度表达导致它们死亡。值得注意的是，APP的家族性阿尔茨海默病（FAD）突变体在神经元中的表达导致（1）APP-BP 1表达的增加，（2）神经元进入细胞周期的S期，和（3）神经元凋亡。此外，APP-BP 1在AD脑的风险区域相对于对照过表达。APP-BP 1代表了第一个真实的“把手”，用于确定AD中出现的细胞周期调控和DNA复制丧失背后的机制。我们认为APP与APP-BP 1的相互作用对正常的脑功能很重要，但在AD中，这两种蛋白质之间的相互作用的调节出错，导致神经元细胞周期调节失败。以下具体目标验证了这一假设： 1.我们将开始定义通过APP-BP 1与APP相互作用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，导致凋亡。 2. APP-BP 1参与了一种新的泛素化相关途径，涉及泛素样分子NEDD 8。我们将使用免疫荧光和共聚焦显微镜，以确定亚细胞结构，其中APP-BP 1，NEDD 8，ASPP 2，和其他分子在泛素化相关的途径居住，在原代神经元的文化和控制和AD死后的大脑。 3.从特定目标1和2的实现获得的数据将表明APP-BP 1介导的信号传导的扰动的特定后果，我们可能期望在死后AD脑中观察到。我们将检验这些预测是否正确。