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Pathogenic mechanisms of presenilin mutation

早老素突变的致病机制

基本信息

批准号：
7383538
负责人：
ROBERT SIMAN
金额：
$ 32.7万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-02-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7383538
关键词：
Adult Adverse effects Age Aging Alzheimer&apos s Disease Amyloid Amyloid Protein AA Amyloid beta-Protein Precursor Amyloid deposition Antibodies Attenuated Behavioral Brain Cerebral hemisphere hemorrhage Clinic Cognition Cognitive Complex Cues Data Defect Dependence Development Disease Endopeptidases Fostering Functional disorder Gene Mutation Gene Targeting Gene Transfer Techniques Genes Genetic Models Genotype Gliosis Goals Growth Hippocampus (Brain)Human Immunization Impaired cognition Impairment In Vitro Induced Mutation Inflammatory Inherited Intervention Knock-in Mouse Laboratory Study Light Link Long-Term Potentiation Mediating Memory Meningoencephalitis Microglia Minocycline Modeling Molecular Molecular Conformation Moods Mus Mutant Strains Mice Mutation Neurobiology Neuronal Plasticity Neurons Onset of illness Pathogenesis Pathology Peptide Hydrolases Perforant Pathway Physiological Physiology Population Pre-Clinical Model Process Protein Overexpression Proteins Regulation Relative (related person)Research Role Stem cells Structure Synapses Synaptic plasticity Syndrome System Tauopathies Testing Therapeutic Therapeutic Agents Transgenes Transgenic Mice Transgenic Model Translational Research age related amyloid pathology base cell type dentate gyrus disease-causing mutation familial Alzheimer disease functional disability inhibitor/antagonist long term memory mouse model mutant nerve stem cell neurobiological mechanism neuroblast neurogenesis neuroinflammation neuropathology novel pre-clinical presenilin presenilin-1 protein aggregation relating to nervous system secretase size stem stoichiometry success tau Proteins tau mutation therapy development

项目摘要

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.

描述（由申请人提供）：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再现了AD的病理和行为特征。它支持了淀粉样蛋白A42蛋白聚集是疾病发作和进展的重要触发因素的假设，并促进了基于减少A42聚集体的治疗策略的发展。然而，转基因模型用于研究AD发病机制和评估候选疗法的效用受到对异位过表达的依赖的限制。作为替代方案，我们引入了小鼠品系，其中基因靶向用于将致病突变“敲入”其内源基因中。我们的研究建立了AD型淀粉样蛋白、tau蛋白和神经炎性病理的唯一小鼠模型，该模型不依赖于异位过表达，并确定了AD发病机制的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绘A 42过度生产的关键机制来扩展这些发现，定义淀粉样蛋白，tau和神经炎性病理学在海马回路中损害适应性可塑性形式的神经生物学作用已知对长期记忆都很重要，并且在AD中受到严重影响，并确定逆转这些病理学和挽救可塑性缺陷的疗法。具体目标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，形成淀粉样蛋白A42蛋白的蛋白酶，并测试突变体PS-1赋予蛋白酶致病构象的假设。具体目标2将检验淀粉样蛋白和tau蛋白病理损害内鼻-海马穿孔通路中突触可塑性的假设，并评价逆转病理和受损可塑性的多种药理学策略。具体目标3将测试突变PS-1通过淀粉样蛋白触发的神经炎症阻碍成年海马神经发生的假设，并确定其可逆性。这项研究将促进我们对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忠实小鼠遗传模型中神经可塑性缺陷的治疗策略。项目叙述：“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AD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。在疾病相关的临床前模型中进行的这种转化研究对于开发旨在延迟AD发作和减缓AD进展的治疗至关重要，并且在临床上成功的可能性很高。