p75NTR proteolysis in Alzheimer's Disease

阿尔茨海默病中的 p75NTR 蛋白水解

• 批准号: 6998329
• 负责人: NATALIE LANDMAN
• 金额: $ 4.49万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6998329
• 关键词: Alzheimer' s disease; SDS polyacrylamide gel electrophoresis; amyloid proteins; biological signal transduction; cell line; electrophysiology; gene mutation; immunocytochemistry; immunoprecipitation; laboratory mouse; mass spectrometry; matrix assisted laser desorption ionization; neural degeneration; neurotoxins; neurotrophic factors; pathologic process; predoctoral investigator; presenilin; protein structure function; proteolysis; receptor expression; second messengers; voltage /patch clamp; western blottings

DESCRIPTION (provided by applicant): Although pathogenic gene products in Alzheimer's disease (AD), i.e. amyloid beta-protein precursor (APP) and presenilins (PS), are expressed throughout the brain, early and most severe neurodegenerative changes in AD manifest in selective populations of neurons, specifically the neurons of the entorhinal cortex and basal forebrain. However, molecular mechanisms that underlie this selective vulnerability remain poorly understood. We have recently reported that the p75 neurotrophin receptor (p75NTR) undergoes PS-dependent APP-like proteolysis (1). The p75NTR is known to be expressed predominantly in AD vulnerable neurons and can affect neuronal survival by serving as a co-receptor for neurotrophins. Thus, we hypothesize that abberant processing of the p75NTR gives rise to p75NTR proteolytic derivatives that may contribute to selective dysfunction and/or degeneration of p75NTR-expressing neurons. Specific Aims are: 1) To examine the functional roles of p75-beta-p and p75-ICD fragments; 2) To determine the effects of PS mutations on proteolysis/signaling of the p75NTR.

描述（由申请人提供）：虽然阿尔茨海默氏病（AD）的致病基因产物，即淀粉样β蛋白前体（APP）和早老素（PS）在整个大脑中表达，但AD中早期和最严重的神经退行性变化表现为选择性的神经退行性改变。神经元群，特别是内嗅皮层和基底前脑的神经元。然而，这种选择性脆弱性背后的分子机制仍然知之甚少。我们最近报道，p75 神经营养素受体 (p75NTR) 会经历 PS 依赖性 APP 样蛋白水解 (1)。已知 p75NTR 主要在 AD 易受影响的神经元中表达，并且可以通过充当神经营养素的共同受体来影响神经元的存活。因此，我们假设 p75NTR 的异常加工产生 p75NTR 蛋白水解衍生物，可能导致表达 p75NTR 的神经元的选择性功能障碍和/或变性。具体目标是： 1) 检查 p75-β-p 和 p75-ICD 片段的功能作用； 2) 确定 PS 突变对 p75NTR 蛋白水解/信号传导的影响。