Pathogenic mechanisms of presenilin mutation

早老素突变的致病机制

• 批准号: 7213539
• 负责人: ROBERT SIMAN
• 金额: $ 39.56万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7213539
• 关键词: Adult; Adverse effects; Age; Aging; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Antibodies; Attenuated; Behavioral; Brain; Cessation of life; Chromosome Pairing; Cognition; Cognitive; Complex; Critical Pathways; Cues; Defect; Dependence; Development; Double Effect; Ectopic Expression; Efferent Pathways; Endopeptidases; Experimental Models; 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; Intervention; Knock-in Mouse; Laboratory Study; Learning; Light; Link; Long-Term Potentiation; Mediating; Memory; Minocycline; Modeling; Molecular; Molecular Conformation; Mus; Mutant Strains Mice; Mutation; Neurobiology; Neuronal Plasticity; Neurons; Onset of illness; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Perforant Pathway; Personal Satisfaction; Phase II Clinical Trials; Physiology; Population; Presenile Alzheimer Dementia; Protein Overexpression; Proteins; Regulation; Research; Research Personnel; Role; Stem cells; Structure; Synapses; Synaptic plasticity; Syndrome; System; Tauopathies; Testing; Therapeutic; Therapeutic Intervention; Transgenes; Transgenic Mice; Transgenic Model; Vaccination; abeta deposition; age related; aging brain; amyloid pathology; astrogliosis; base; cell type; disease-causing mutation; gamma secretase; inhibitor/antagonist; long term memory; mood regulation; mouse model; mutant; nerve stem cell; neural circuit; neuroblast; neurogenesis; neuroinflammation; neuropathology; neurophysiology; pre-clinical; presenilin; presenilin-1; programs; relating to nervous system; secretase; size; stem; stoichiometry; tau Proteins; tau mutation

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.

描述（由申请人提供）：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再现了AD的病理和行为特征。它支持了淀粉样蛋白Abeta 42蛋白的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Abeta沉积的治疗策略的发展。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，我们引入了小鼠实验模型，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型淀粉样蛋白和tau神经病理学的唯一小鼠模型，该模型不依赖于过度表达，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Abeta 42过度产生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中的适应性可塑性形式中的作用，已知这些适应性可塑性形式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并挽救可塑性缺陷的疗法。具体目标1将确定突变PS-1在小鼠脑γ-分泌酶（形成淀粉样蛋白Abeta 42蛋白的蛋白酶）中引起的结构和功能变化，并测试突变PS-1赋予蛋白酶致病构象的假设。具体目标2将测试的假设，即淀粉样蛋白和tau蛋白的病理损害突触可塑性的穿通通路，并评估两种药理学策略，逆转这些缺陷。具体目标3将检验突变PS-1通过淀粉样蛋白介导的神经炎症损害成年海马神经发生的假设，并确定其药理学可逆性。这项研究将促进我们对FAD相关基因突变致病机制的理解，并评估旨在减缓FAD忠实小鼠遗传模型发病和进展的治疗策略。