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¿-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A¿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A¿42聚集的治疗策略的发展。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，我们引入了一些小鼠品系，在这些品系中，基因靶向被用来“敲入”致病突变到它们的内源性基因中。我们的研究建立了唯一不依赖于异位过表达的AD型淀粉样蛋白、tau蛋白和神经炎症病理的小鼠模型，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a¿42过度产生的关键机制来扩展这些发现，定义淀粉样蛋白、tau蛋白和神经炎症病理在海马回路中损害适应性可塑性形式的神经生物学作用，这些适应性可塑性形式对长期记忆和AD严重影响都很重要，并确定逆转这些病理和挽救可塑性缺陷的治疗方法。特异性目标1将确定突变PS-1在小鼠大脑中引起的结构和功能变化？-分泌酶，一种形成淀粉样蛋白A¿42的蛋白酶，并测试突变的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病理损害内啡肽-海马穿通通路突触可塑性的假设，并评估多种逆转病理和受损可塑性的药理学策略。特异性目的3将验证突变体PS-1通过淀粉样蛋白引发的神经炎症阻碍成人海马神经发生的假设，并确定其可逆性。本研究将促进我们对FAD相关基因突变的分子和神经生物学机制的理解，并在忠实的FAD小鼠遗传模型中评估几种旨在减少神经可塑性缺陷的治疗策略。项目描述：“早老素突变的致病机制”：拟议的研究将使用一种新的和忠实的小鼠遗传模型来推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。它将促进对阿尔茨海默病认知和行为综合征的神经生物学机制的基本理解，并评估针对这些神经生物学过程的多种候选治疗策略。这种疾病相关临床前模型的转化研究对于开发旨在延缓阿尔茨海默病发病和减缓其进展的治疗方法至关重要，并且很有可能在临床取得成功。

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.