Pathogenic mechanisms of presenilin mutation

描述(申请人提供)：编码早老素1和2(PS-1和PS-2)以及β-淀粉样前体蛋白(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概括了AD的病理和行为特征。它支持了淀粉样蛋白Abet42蛋白的聚集是疾病发生和发展的重要触发因素的假设，并促进了基于减少Abeta沉积的治疗策略的开发。然而，转基因模型用于研究AD发病机制和评估候选治疗方法的有效性受到对异位过度表达的依赖的限制。作为另一种选择，我们引入了小鼠实验模型，在该模型中，基因打靶被用来将致病突变“敲入”它们的内源基因。我们的研究建立了唯一不依赖于过度表达的AD类型淀粉样蛋白和tau蛋白神经病理的小鼠模型，并确定了AD发病机制的神经生物学和分子机制。这项拟议的研究将扩展这些发现，在分子水平上描绘Abeta42过度生产的关键机制，定义淀粉样蛋白和tau病理在神经系统适应性可塑性受损形式中的作用，已知的神经系统适应性可塑性既对长期记忆重要，又严重影响AD，并确定逆转这些病理并挽救可塑性缺陷的治疗方法。具体目标1将确定突变的PS-1在小鼠大脑伽马分泌酶中引起的结构和功能变化，并检验突变的PS-1赋予蛋白酶致病构象的假设。特定目标2将验证淀粉样蛋白和tau病理损害穿支通路中突触可塑性的假设，并评估两种逆转这些缺陷的药物策略。具体目标3将测试突变PS-1通过淀粉样蛋白介导的神经炎症损害成年海马区神经发生的假设，并确定其药理学可逆性。这项拟议的研究将促进我们对FAD相关基因突变的致病机制的理解，并评估旨在减缓FAD小鼠遗传模型中FAD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.