Pathogenic mechanisms of presenilin mutation

描述（由申请人提供）：编码早老素1和2 （PS-1和PS-2）和β -淀粉样蛋白前体蛋白（APP）的基因突变是家族性早发性阿尔茨海默病（FAD）的主要原因。这些基因突变在转基因小鼠中的过度表达再现了阿尔茨海默病的病理和行为特征。它支持了淀粉样蛋白Abeta 42的聚集是疾病发生和进展的重要触发因素的假设，并促进了基于减少Abeta沉积的治疗策略的发展。然而，转基因模型在研究阿尔茨海默病发病机制和评估候选疗法方面的应用受到对异位过表达依赖的限制。作为替代方案，我们引入了小鼠实验模型，其中基因靶向用于将致病突变“敲入”其内源性基因。我们的研究建立了唯一不依赖于过表达的AD型淀粉样蛋白和tau神经病变的小鼠模型，并确定了AD发病的核心神经生物学和分子机制。拟议的研究将通过在分子水平上描述Abeta42过度生产的关键机制来扩展这些发现，定义淀粉样蛋白和tau病理在损害神经系统适应性可塑性形式中的作用，这些形式已知对长期记忆很重要，对AD有严重影响，并确定逆转这些病理和挽救可塑性缺陷的治疗方法。Specific Aim 1将确定突变PS-1在小鼠脑γ -分泌酶（形成淀粉样蛋白Abeta 42的蛋白酶）中引起的结构和功能变化，并验证突变PS-1赋予蛋白酶致病构象的假设。特异性目标2将验证淀粉样蛋白和tau病理损害穿孔通路突触可塑性的假设，并评估逆转这些缺陷的两种药理学策略。特异性目的3将验证突变体PS-1通过淀粉样蛋白介导的神经炎症损害成人海马神经发生的假设，并确定其药理学可逆性。该研究将促进我们对FAD相关基因突变致病机制的理解，并评估旨在减缓FAD忠实小鼠遗传模型的发病和进展的治疗策略。

DESCRIPTION (provided by applicant): Mutations in the genes encoding presenilins 1 and 2 (PS-1 and PS-2) and the beta-amyloid precursor protein (APP) are the leading cause of familial, early-onset Alzheimer's disease (FAD). Over-expression of these gene mutations in transgenic mice recapitulates pathological and behavioral features of AD. It has supported the hypothesis that aggregation of the amyloid Abeta 42 protein is an important trigger for disease onset and progression, and fostered the development of therapeutic strategies based on reducing Abeta deposition. However, the utility of transgenic models for investigating AD pathogenesis and evaluating candidate therapies is constrained by the dependence on ectopic over-expression. As an alternative, we introduced mouse experimental models in which gene targeting was used to "knock-in" disease-causing mutations into their endogenous genes. Our studies established the only mouse model for AD-type amyloid and tau neuropathologies that does not rely on over-expression, and identified neurobiological and molecular mechanisms central to AD pathogenesis. The proposed research would extend these findings by delineating at the molecular level a key mechanism for Abeta42 overproduction, defining the role for amyloid and tau pathologies in impairing forms of adaptive plasticity in neural systems known to be both important for long- term memory and severely impacted in AD, and identifying therapies that reverse these pathologies and rescue the plasticity deficits. Specific Aim 1 will identify structural and functional changes caused by mutant PS-1 in the mouse brain gamma-secretase, the protease that forms the amyloid Abeta 42 protein, and test the hypothesis that mutant PS-1 confers a pathogenic conformation on the protease. Specific Aim 2 will test the hypothesis that the amyloid and tau pathologies impair synaptic plasticity in the perforant pathway, and evaluate two pharmacologic strategies for reversing these defects. Specific Aim 3 will test the hypothesis that mutant PS-1 impairs neurogenesis in the adult hippocampus through amyloid-mediated neuroinflammation, and determine its pharmacologic reversibility. The proposed research will advance our understanding of pathogenic mechanisms of FAD-linked gene mutations and evaluate therapeutic strategies aimed at slowing the onset and progression in a faithful mouse genetic model of FAD.