Presenilins, Apoptosis, and Cortical Degeneration

描述（由申请人提供）：早发性家族性阿尔茨海默病是阿尔茨海默病最具侵袭性的形式，早在30多岁时就发生;这些患者通常携带早老素-1（PS1）和早老素-2（PS2）突变，表现出记忆丧失和痴呆的加速发作，以及解决问题、语言和其他认知能力的进行性损伤。他们的大脑通常以老年斑和神经元缠结的积累、皮质和海马组织的选择性收缩以及侧脑室和第三脑室体积的增大为特征。 由于PS1和PS2的常规敲除导致早期胚胎死亡，这不幸地阻止了对它们在成年期的体内功能的分析，因此早老蛋白及其在成年脑中的协调相互作用的作用是未知的。此外，早老素的突变几乎都是错义突变;这导致了流行的概念，即“功能获得”机制可能是早发性AD的分子发病机制的主要解释。在这个提议中，我们开始研究PS1和PS2都在维持成人大脑结构和功能中起关键作用的假设。我们拟利用条件性基因敲除技术研究早老素、细胞凋亡和脑变性之间的关系。第一组主要实验将集中在条件性双基因敲除小鼠的生产和基本表征上。第二组主要的实验将进行检查是否以及如何删除两个早老素导致成年前脑细胞凋亡和变性的增加。了解早老素在成人大脑中的作用可能为我们提供新的途径来延缓或预防衰老过程中脑退行性疾病的发病机制。

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.