Presenilins, Apoptosis, and Cortical Degeneration

早老素、细胞凋亡和皮质变性

• 批准号: 7097910
• 负责人: Joe Z Tsien
• 金额: $ 32.33万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7097910
• 关键词: Alzheimer' s disease; aging; apoptosis; disease /disorder model; disease /disorder onset; frontal lobe /cortex; gene mutation; genetic disorder; genetically modified animals; immunocytochemistry; laboratory mouse; molecular pathology; neural degeneration; neurofibrillary tangles; neurogenesis; neurogenetics; neuropathology; presenilin; prosencephalon; tau proteins

DESCRIPTION (provided by applicant): Early-onset familial Alzheimer's disease is the most aggressive form of Alzheimer's, striking patients as early as their 30s; Those patients, typically carrying mutations in presenilin-1 (PS1) and presenilin-2 (PS2), exhibit accelerated onset of memory loss and dementia, progressive impairments in problem solving, language, and other cognitive abilities. Their brains are usually hallmarked by accumulations of senile plaques and neurofibrillary tangles, selective shrinkage of cortical and hippocampal tissues, and enlargement of lateral and third ventricle volume. Since conventional knockout of both PS1 and PS2 leads to early embryonic lethality which unfortunately prevents the analysis of their in vivo function in the adulthood, the role of presenilins and their coordinated interactions in adult brain is not known. Moreover, mutations in the presenilins are nearly all missense mutations; this has led to the popular notion that a "gain-of-function" mechanism may be the leading explanation for the molecular pathogenesis of the early-onset AD. In this proposal, we set to examine the hypothesis that both PS1 and PS2 are critically involved in maintaining the adult brain structure and function. We propose to use conditional knockout technique to study the relationship of presenilins, apoptosis, and brain degeneration. The first major set of experiments will focus on the production and basic characterization of the conditional double knockout mice. The second major set of experiments will be conducted to examine whether and how the deletion of both presenilins leads to increased apoptosis and degeneration of adult forebrain. Understanding the role of presenilins in the adult brain may provide us with new avenues to delay or prevent the pathogenesis of brain degenerative disease during ageing.

描述（由申请人提供）：早期发作的家族性阿尔茨海默氏病是阿尔茨海默氏症最激进的形式，早在30多岁时就引人注目。这些患者通常在Presenilin-1（PS1）和Presenilin-2（PS2）中携带突变，表现出加速记忆力丧失和痴呆症的发作，问题解决，语言和其他认知能力的渐进障碍。它们的大脑通常以老年斑块和神经纤维缠结，皮质和海马组织的选择性收缩以及侧面和第三心室体积的扩大来标志性。 由于常规敲除PS1和PS2都会导致早期的胚胎致死性，这不幸地阻止了其在成年期对其体内功能的分析，因此尚不清楚Presenilins及其在成人大脑中的协调相互作用的作用。此外，老龄蛋白的突变几乎是所有的错义突变。这导致了人们普遍的观念，即“功能获得”机制可能是早发AD的分子发病机理的主要解释。在此提案中，我们开始研究PS1和PS2都与维持成人大脑结构和功能的假设。我们建议使用条件敲除技术研究presenilins，凋亡和脑变性的关系。第一组主要的实验集将集中于条件双基因敲除小鼠的生产和基本表征。将进行第二组主要的实验集，以检查两种老年蛋白的缺失以及如何导致成人前脑的凋亡和变性增加。了解老龄素在成年大脑中的作用可能会为我们提供新的途径，以延迟或防止衰老期间脑退行性疾病的发病机理。