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）：尽管阿尔茨海默氏病（AD）中的致病基因产物，即淀粉样蛋白β-蛋白蛋白前体（APP）和寄生虫（PS）在整个大脑中表达，早期和最严重的神经退行性变化在AD中的神经退行性变化，在神经元的精选神经元中，具体的神经元和基础上，均具有神经元和基础。但是，这种选择性脆弱性的基础的分子机制仍然很少理解。我们最近报道说，p75神经营养蛋白受体（P75NTR）经历了PS依赖性应用类样蛋白水解（1）。已知P75NTR主要在AD脆弱的神经元中表达，并且可以通过作为神经营养蛋白的共受体来影响神经元存活。因此，我们假设p75NTR的宽大处理会产生P75NTR蛋白水解衍生物，这可能有助于选择性功能障碍和/或p75NTR表达神经元的变性。具体目的是：1）检查p75-beta-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。