Presenilin dysfunction in the brain

大脑早老素功能障碍

基本信息

  • 批准号:
    8294529
  • 负责人:
  • 金额:
    $ 35.8万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
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.

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Raymond J Kelleher其他文献

Raymond J Kelleher的其他文献

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{{ truncateString('Raymond J Kelleher', 18)}}的其他基金

Research Mentoring in Neurology and Translational Research on Alzheimers Disease
神经病学研究指导和阿尔茨海默病转化研究
  • 批准号:
    9899333
  • 财政年份:
    2016
  • 资助金额:
    $ 35.8万
  • 项目类别:
Presenilin dysfunction in the brain
大脑早老素功能障碍
  • 批准号:
    8642686
  • 财政年份:
    2011
  • 资助金额:
    $ 35.8万
  • 项目类别:
Presenilin dysfunction in the brain
大脑早老素功能障碍
  • 批准号:
    8162930
  • 财政年份:
    2011
  • 资助金额:
    $ 35.8万
  • 项目类别:
Presenilin dysfunction in the brain
大脑早老素功能障碍
  • 批准号:
    8453481
  • 财政年份:
    2011
  • 资助金额:
    $ 35.8万
  • 项目类别:
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
  • 财政年份:
    2011
  • 资助金额:
    $ 35.8万
  • 项目类别:
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:
    9187520
  • 财政年份:
    2011
  • 资助金额:
    $ 35.8万
  • 项目类别:
MicroRNAs in Synaptic Plasticity and Behaviors Relevant to Autism
MicroRNA 在突触可塑性和与自闭症相关行为中的作用
  • 批准号:
    8004919
  • 财政年份:
    2009
  • 资助金额:
    $ 35.8万
  • 项目类别:
MicroRNAs in Synaptic Plasticity and Behaviors Relevant to Autism
MicroRNA 在突触可塑性和与自闭症相关的行为中的作用
  • 批准号:
    8585883
  • 财政年份:
    2009
  • 资助金额:
    $ 35.8万
  • 项目类别:
MicroRNAs in Synaptic Plasticity and Behaviors Relevant to Autism
MicroRNA 在突触可塑性和与自闭症相关的行为中的作用
  • 批准号:
    8197401
  • 财政年份:
    2009
  • 资助金额:
    $ 35.8万
  • 项目类别:
MicroRNAs in Synaptic Plasticity and Behaviors Relevant to Autism
MicroRNA 在突触可塑性和与自闭症相关的行为中的作用
  • 批准号:
    8390489
  • 财政年份:
    2009
  • 资助金额:
    $ 35.8万
  • 项目类别:

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