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)以及淀粉样前体蛋白(APP)的基因突变是家族性阿尔茨海默病(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A？42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A？42聚集的治疗策略的开发。然而，转基因模型在研究AD发病机制和评估候选治疗方法方面的实用性受到异位过度表达依赖性的限制。作为另一种选择，我们引入了小鼠品系，在这些品系中，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异位过度表达的AD类淀粉样蛋白、tau蛋白和神经炎性病理的小鼠模型，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A？42过度产生的关键机制，定义淀粉样蛋白、tau蛋白和神经炎性病理在损害海马回路适应性可塑性形式中的神经生物学作用，已知这些可塑性对长期记忆很重要，并在AD中受到严重影响，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在小鼠大脑中引起的结构和功能变化，该酶是形成淀粉样蛋白A？42蛋白的蛋白酶，并检验突变的PS-1赋予该酶的致病构象的假设。特定目的2将验证淀粉样蛋白和tau病理损害内脏-海马穿孔通路突触可塑性的假说，并评估逆转该病理和可塑性受损的多种药物策略。具体目标3将测试突变PS-1通过淀粉样蛋白引发的神经炎症阻碍成年海马区神经发生的假设，并确定其可逆性。这项拟议的研究将促进我们对FAD相关基因突变的分子和神经生物学机制的理解，并评估几种旨在减少FAD小鼠遗传模型中神经可塑性缺陷的治疗策略。项目简介：“早老素突变的致病机制”：这项拟议的研究将使用一种新颖而可靠的小鼠遗传模型来促进我们对某些基因突变导致遗传性阿尔茨海默病的机制的理解。它将促进对AD认知和行为综合征潜在的神经生物学机制的基本了解，并评估针对这些神经生物学过程的多种候选治疗策略。这种与疾病相关的临床前模型的转化研究对于旨在延缓AD发病和减缓AD进展的治疗方法的开发至关重要，临床上成功的可能性很高。

DESCRIPTION (provided by applicant): Mutations in the genes encoding presenilins 1 and 2 (PS-1 and PS-2) and the ¿-amyloid precursor protein (APP) are the leading cause of familial Alzheimer's disease (FAD). Overexpression of these gene mutations in transgenic mice recapitulates pathological and behavioral features of AD. It has supported the hypothesis that aggregation of the amyloid A¿42 protein is an important trigger for disease onset and progression, and fostered the development of therapeutic strategies based on reducing A¿42 aggregates. However, the utility of transgenic models for investigating AD pathogenesis and evaluating candidate therapies is constrained by the dependence on ectopic overexpression. As an alternative, we introduced mouse lines 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, tau, and neuroinflammatory pathologies that does not rely on ectopic overexpression, 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 A¿42 overproduction, defining neurobiological roles for amyloid, tau, and neuroinflammatory pathologies in impairing forms of adaptive plasticity in hippocampal circuits 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 ?-secretase, the protease that forms the amyloid A¿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 entorhino-hippocampal perforant pathway, and evaluate multiple pharmacologic strategies for reversing the pathology and impaired plasticity. Specific Aim 3 will test the hypothesis that mutant PS-1 hinders neurogenesis in the adult hippocampus through amyloid-triggered neuroinflammation, and determine its reversibility. The proposed research will advance our understanding of molecular and neurobiological mechanisms of FAD-linked gene mutations and evaluate several therapeutic strategies aimed at reducing neuroplasticity deficits in a faithful mouse genetic model of FAD. Project Narrative: "Pathogenic mechanisms of presenilin mutation": The proposed research will use a novel and faithful mouse genetic model to advance our understanding mechanisms by which certain gene mutations cause inherited Alzheimer's disease. It will promote basic understanding of the neurobiological mechanisms underlying the cognitive and behavioral syndrome of AD, and evaluate multiple candidate therapeutic strategies that target these neurobiological processes. This translational research in a disease-relevant preclinical model is crucial to the development of therapies aimed at delaying the onset and slowing the progression of AD with a high likelihood of success in the clinic.