Presenilin dysfunction in the brain

大脑早老素功能障碍

• 批准号: 8162930
• 负责人: Raymond J Kelleher
• 金额: $ 36万
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8162930
• 关键词: Accounting; Adult; Affect; Age-Months; Alleles; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Amyloid deposition; Brain; Cell Culture System; Cellular Neurobiology; Cessation of life; Clinical; Collaborations; Cultured Cells; Data; Defect; Dementia; Deposition; Disease; Dominant-Negative Mutation; Embryo; Exhibits; Fibroblasts; Functional disorder; Gene Dosage; Generations; Genes; Goals; Gossypium; Human; Impaired cognition; Impairment; Inherited; Investigation; Knock-in Mouse; Knock-out; Knockout Mice; Laboratories; Lead; Learning; Light; Link; Measures; Mediating; Memory; Molecular; Molecular Neurobiology; Morphology; Mus; Mutation; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Pathogenesis; Patients; Perinatal; Phenotype; Presenile Alzheimer Dementia; Process; Production; Relative (related person); Role; Series; Severities; Synapses; Synaptic Transmission; Synaptic plasticity; System; Testing; Transgenes; Wool; age related; amyloid pathology; amyloid peptide; base; comparative; conditioned fear; early onset; experience; familial Alzheimer disease; gain of function; genetic pedigree; insight; loss of function; medical schools; morris water maze; multidisciplinary; mutant; neurogenesis; neuronal survival; neuropathology; notch protein; novel strategies; null mutation; postnatal; presenilin; presenilin-1; presenilin-2; secretase; synaptic function

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common cause of neurodegeneration and dementia. Mutations in presenilin 1 (PS1) and presenilin 2 (PS2) account for ~90% of all identified causative mutations in familial AD (FAD), highlighting the importance of presenilins (PS) in AD pathogenesis. However, the molecular mechanisms by which PS mutations lead to neuronal dysfunction and death in FAD is a key unresolved question. Pathogenic mutations have been found to impair PS function and promote overproduction of ?-amyloid peptides in cell culture systems, but the relative contributions of loss-of-function and gain-of-function mechanisms to FAD pathogenesis have not been fully defined. Through the generation and analysis of conditional knockout mice lacking PS function in the adult brain, we previously identified essential roles for PS in synaptic function, memory and neuronal survival in the adult brain. Based on these and other observations, we recently proposed that loss of essential neuronal functions of PS may be a primary cause of dementia and neurodegeneration in FAD. In this new competing R01 application, we test this hypothesis by examining the impact of FAD mutations on essential PS functions in the developing and adult brains. We recently identified a PS1 mutation (L435F) in an early-onset FAD pedigree with cotton wool plaque neuropathology, and found that this mutation causes a nearly complete loss of ?-secretase activity in PS-deficient mouse embryo fibroblasts. Moreover, we recently found that PS1 harboring pathogenic mutations can modulate the activity of wild-type PS1 in a dominant-negative manner. In the first Specific Aim, we propose a multidisciplinary analysis of the effects of the PS1 L435F mutation on neurogenesis in the developing mouse brain and synaptic function, memory and neuronal survival in the adult brain. In particular, we will determine whether this mutation can rescue the defects in these processes caused by complete PS inactivation, and we will also assess the role of PS gene dosage in determining the phenotypic consequences of the mutation. In the second Specific Aim, we will investigate whether the mutant PS1 bearing the L435F mutation can modulate the activity of wild-type PS1 in the developing and adult brains. We will compare the relative effects of PS1 L435F and null mutations on ?-secretase activity, A? production and A? deposition in cultured neurons and/or the adult brain. We will then extend our analysis to the effects of additional FAD mutations on ?-secretase activity and synaptic function in a primary neuronal culture system. Completion of our proposed Specific Aims will provide mechanistic insight into the effects of pathogenic mutations on PS function in the brain, where the pathogenesis of AD ultimately occurs. Our long-term goal is to understand how pathogenic mutations alter PS function to provoke dementia and neurodegeneration in AD, and to unravel the mechanisms by which loss of PS function produces synaptic dysfunction, cognitive decline and neurodegeneration. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the most common neurodegenerative disorder, and mutations in the presenilin genes are the most common cause of inherited forms of the disease. Pathogenic presenilin mutations have been proposed to cause dementia and neurodegeneration through loss-of-function and gain-of-function mechanisms, but the impact of pathogenic mutations on presenilin function in the brain remains unclear. In this application, we propose a multidisciplinary investigation of the mechanisms by which pathogenic presenilin mutations lead to dementia and neurodegeneration, focusing on essential neuronal functions of presenilins in the developing and adult brain. Completion of our proposed study will provide important insights into AD pathogenesis and may identify novel approaches to therapy for this devastating disease.

描述（由申请人提供）：阿尔茨海默氏病（AD）是神经变性和痴呆的最常见原因。早老素 1 (PS1) 和早老素 2 (PS2) 突变约占家族性 AD (FAD) 中所有已知致病突变的 90%，这凸显了早老素 (PS) 在 AD 发病机制中的重要性。然而，PS 突变导致 FAD 神经元功能障碍和死亡的分子机制是一个尚未解决的关键问题。已发现致病性突变会损害 PS 功能并促进细胞培养系统中 β-淀粉样肽的过量产生，但功能丧失和功能获得机制对 FAD 发病机制的相对贡献尚未完全确定。通过生成和分析成年大脑中缺乏 PS 功能的条件敲除小鼠，我们之前确定了 PS 在成年大脑中突触功能、记忆和神经元存活中的重要作用。基于这些和其他观察，我们最近提出 PS 基本神经元功能的丧失可能是 FAD 痴呆和神经变性的主要原因。在这个新的竞争性 R01 应用中，我们通过检查 FAD 突变对发育中和成人大脑中基本 PS 功能的影响来检验这一假设。我们最近在棉毛斑块神经病理学的早发性 FAD 谱系中发现了 PS1 突变 (L435F)，并发现该突变导致 PS 缺陷的小鼠胚胎成纤维细胞几乎完全丧失 β-分泌酶活性。此外，我们最近发现携带致病性突变的PS1可以以显性失活的方式调节野生型PS1的活性。在第一个具体目标中，我们提出对 PS1 L435F 突变对发育中的小鼠大脑神经发生以及成年大脑中的突触功能、记忆和神经元存活的影响进行多学科分析。特别是，我们将确定该突变是否可以挽救由 PS 完全失活引起的这些过程中的缺陷，并且我们还将评估 PS 基因剂量在确定突变的表型后果中的作用。在第二个具体目标中，我们将研究带有 L435F 突变的突变型 PS1 是否可以调节发育中和成人大脑中野生型 PS1 的活性。我们将比较 PS1 L435F 和无效突变对 β-分泌酶活性的相对影响，A？生产和A？沉积在培养的神经元和/或成人大脑中。然后，我们将分析扩展到原代神经元培养系统中额外的 FAD 突变对 β-分泌酶活性和突触功能的影响。完成我们提出的具体目标将为致病性突变对大脑 PS 功能的影响提供机制上的见解，而 AD 的发病机制最终发生在大脑中。我们的长期目标是了解致病性突变如何改变 PS 功能从而引发 AD 中的痴呆和神经变性，并揭示 PS 功能丧失导致突触功能障碍、认​​知能力下降和神经变性的机制。 公共健康相关性：阿尔茨海默病 (AD) 是最常见的神经退行性疾病，早老素基因突变是导致该疾病遗传形式的最常见原因。致病性早老素突变已被认为可通过功能丧失和功能获得机制引起痴呆和神经变性，但致病性突变对大脑早老素功能的影响仍不清楚。在本申请中，我们提出对致病性早老素突变导致痴呆和神经变性的机制进行多学科研究，重点关注早老素在发育中和成人大脑中的基本神经元功能。完成我们提出的研究将为 AD 发病机制提供重要见解，并可能确定治疗这种破坏性疾病的新方法。