Mechanisms of brain phenotypes caused by FAD-linked Presenilin-1 Mutations

FAD 相关 Presenilin-1 突变引起脑表型的机制

• 批准号: 9272013
• 负责人: Raymond J Kelleher
• 金额: $ 59.16万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9272013
• 关键词: Abeta synthesis; Adult; Alleles; Alzheimer' s Disease; Autophagocytosis; Behavioral; Biological Preservation; Brain; Catalytic Domain; Cerebrum; Clinical; Complex; Data; Dementia; Development; Disease; Functional disorder; Gene Dosage; Generations; Genes; Heterozygote; Hippocampus (Brain); Histologic; Impairment; Inflammatory; Inherited; Knock-in; Knock-in Mouse; Knockout Mice; Lead; Learning; Link; Memory; Memory impairment; Molecular; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Pathogenesis; Pathogenicity; Patients; Peptide Hydrolases; Phenotype; Physiological; Play; Process; Reporting; Role; Series; Synapses; Synaptic plasticity; System; Testing; Transgenic Mice; Transgenic Organisms; Treatment Efficacy; Work; abeta accumulation; abeta deposition; aging brain; amyloid precursor protein processing; beta catenin; comparative; effective therapy; familial Alzheimer disease; gamma secretase; in vivo; loss of function; mouse model; multidisciplinary; mutant; neurodegenerative phenotype; neuronal survival; novel; null mutation; overexpression; presenilin; presenilin-1; presenilin-2; synaptic function

Project Summary/Abstract Mutations in the PSEN1 and PSEN2 genes encoding Presenilin-1 (PS1) and Presenilin-2 (PS2) are the most common cause of familial Alzheimer's disease (FAD), highlighting the importance of Presenilin function in disease pathogenesis, but the underlying mechanisms remain unresolved. Aberrant APP processing by γ- secretase and γ-secretase-independent activities of PS1 have been implicated in FAD pathogenesis. Our recent work has shown surprisingly that pathogenic mutations in PS1 can inactivate its function as the catalytic subunit of the γ-secretase complex and produce FAD-related phenotypes through a loss-of-function mechanism. To assess the effects of FAD mutations in vivo, particularly in the brain where the pathogenic process occurs, we generated two independent lines of Psen1 knock-in (KI) mice that precisely reproduce chromosomal PSEN1 mutations identified in FAD patients. Our analysis revealed phenotypes in the resulting homozygous KI mice indistinguishable from those caused by a Psen1 null mutation, accompanied by essentially complete loss of γ-secretase activity in the brain. Heterozygosity for the Psen1 L435F KI mutation produced deficits in hippocampal short- and long-term synaptic plasticity and hippocampal learning and memory reminiscent of those caused by conditional inactivation of Presenilins in the adult brain. Intriguingly, heterozygous KI mice also displayed elevation of the cortical Aβ42/Aβ40 ratio and exacerbation of cortical Aβ deposition on a mutant APP transgenic background. Moreover, the Psen1 L435F KI mutation was unable to support neuronal survival in the aging brain, triggering widespread cerebral cortical neurodegeneration. In this competing renewal application, we propose to investigate the important questions of whether and to what extent these synaptic, behavioral, and neurodegenerative phenotypes caused by the FAD mutation are attributable to aberrant APP processing and impaired γ-secretase activity, or alternatively to APP-independent and/or γ-secretase-independent functions of PS1. We propose to perform multidisciplinary molecular, synaptic, behavioral, and histological analysis using novel mouse models to understand the contributions of APP processing and γ-secretase-independent activity to Presenilin function and FAD-related dysfunction in the adult brain. The results of our studies will have significant impact on understanding of FAD pathogenesis and strategies to devise effective therapies.

项目概要/摘要 编码 Presenilin-1 (PS1) 和 Presenilin-2 (PS2) 的 PSEN1 和 PSEN2 基因的突变最为常见。 家族性阿尔茨海默病 (FAD) 的常见病因，强调了早老素功能在 疾病的发病机制，但潜在的机制仍未解决。 γ-异常APP处理 PS1 的分泌酶和不依赖于 γ 分泌酶的活性与 FAD 发病机制有关。我们的 最近的工作令人惊讶地表明，PS1 的致病性突变可以使其催化功能失活。 γ-分泌酶复合物的亚基并通过功能丧失产生 FAD 相关表型 机制。评估 FAD 突变在体内的影响，特别是在致病基因所在的大脑中 过程发生后，我们生成了两个独立的 Psen1 敲入 (KI) 小鼠品系，它们能够精确繁殖 FAD 患者中发现染色体 PSEN1 突变。我们的分析揭示了结果中的表型 纯合 KI 小鼠与 Psen1 无效突变引起的小鼠无法区分，并伴有 大脑中γ-分泌酶活性基本上完全丧失。 Psen1 L435F KI 突变的杂合性 造成海马短期和长期突触可塑性以及海马学习的缺陷 记忆让人想起成人大脑中早老素有条件失活所引起的记忆。有趣的是， 杂合 KI 小鼠还表现出皮质 Aβ42/Aβ40 比率升高和皮质 Aβ 恶化 突变APP转基因背景上的沉积。此外，Psen1 L435F KI 突变无法 支持衰老大脑中神经元的存活，引发广泛的大脑皮层神经变性。在这个 竞争性更新申请，我们建议调查以下重要问题：是否以及更新内容 FAD 突变引起的这些突触、行为和神经退行性表型的程度 可归因于 APP 处理异常和 γ-分泌酶活性受损，或者与 APP 无关 和/或 PS1 的 γ-分泌酶独立功能。我们建议进行多学科分子、突触、 使用新型小鼠模型进行行为和组织学分析，以了解 APP 的贡献 加工和 γ 分泌酶独立活性对成人早老素功能和 FAD 相关功能障碍的影响 脑。我们的研究结果将对 FAD 发病机制的理解和 制定有效疗法的策略。