Mechanisms of synapse dysfunction in Alzheimer's disease

阿尔茨海默病突触功能障碍的机制

基本信息

  • 批准号:
    7911479
  • 负责人:
  • 金额:
    $ 9.22万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-12-15 至 2009-11-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): A prominent theory about Alzheimer's disease (AD) proposes that early cognitive deficits are due to subtle alterations in synaptic transmission, but specific AD-related changes in synaptic transmission are not well understood. In order to better understand the role of synaptic deficits during the early stages of AD, we must study the effects of AD-related proteins on synaptic transmission in a mammalian central nervous system preparation. Two proteins that have been strongly implicated in AD-related synaptic dysfunction are amyloid precursor protein (APP) and presenilin. We have recently shown that overexpression of APP depresses synaptic transmission through both pre- and postsynaptic mechanisms, and that this depression depends on production of amyloid beta peptide (A?). It remains to be determined which specific isoform of A? (A?40 or A?42) is the relevant ligand, and which surface receptors (if any) is responsible mediating its effects. Presenilin is a critical component of ?-secretase, an enzyme required for A? production. Presenilin is also known to influence storage and release of calcium from internal stores. Changes in the levels of intracellular calcium are a critical signal for many pathways inside the cell, including signals that tell neurons how much neurotransmitter to release when they fire an action potential. Thus, changes in presenilin levels or function could affect synaptic transmission by altering either A? production or intracellular calcium levels. Our long-term objective is to develop a model system that will allow us to investigate the molecules and signaling pathways that are responsible for synaptic dysfunction underlying cognitive deficits associated with AD. We will focus initially on PS1 and APP. Specific Aim 1 of this proposal is to identify the role of wild-type PS1 in synaptic transmission and test the hypothesis that expression of Familial AD-linked mutant PS1 alters synaptic transmission. Specific Aim 2a is to determine whether elevated levels of secreted A?42 depress transmission at excitatory synapses, and whether either A240 or the caspase cleavage-resistant mutant APPD664A can reduce this depression. Specific Aim 2b is to identify the role of nicotinic acetylcholine receptors, NMDA receptors, group I metabotropic glutamate receptors, and insulin receptors in APP-mediated depression of synaptic transmission. Our experimental strategy is to use electrophysiological and optical imaging techniques to identify specific changes in neurotransmission produced by virally-mediated overexpression of wild-type and mutant forms of presenilin, APP, and APP-cleavage products in cultured mouse hippocampal neurons. Our lab has extensive experience studying the effects of virally-mediated overexpression of a variety of proteins on synaptic transmission in cultured hippocampal neurons, and is, therefore, in an excellent position to exploit this system to identify the effects of AD-related proteins on neurotransmission. These studies will provide molecular targets for novel therapies to improve cognitive function and delay further neurodegeneration in patients with early Alzheimer's disease. Alzheimer's disease is the most common cause of cognitive deficits in the aged, and is thought to begin with synaptic dysfunction. Understanding the cellular and molecular mechanisms underlying this synaptic dysfunction will provide new targets for therapeutic treatments to relieve symptoms, and slow or perhaps even stop disease progression.
描述(由申请人提供):关于阿尔茨海默病(AD)的一个重要理论提出,早期认知缺陷是由于突触传递的细微变化,但突触传递中与AD相关的具体变化尚未得到很好的理解。为了更好地了解突触缺陷在AD早期阶段的作用,我们必须研究AD相关蛋白对哺乳动物中枢神经系统突触传递的影响。两种与AD相关的突触功能障碍密切相关的蛋白质是淀粉样前体蛋白(APP)和早老素。我们最近发现APP的过度表达通过突触前和突触后机制抑制突触传递,并且这种抑制依赖于淀粉样β肽(A?)的产生。它仍然有待确定的具体亚型A?(A?40还是A?42)是相关的配体,以及哪些表面受体(如果有的话)负责介导其作用。早老素是一种重要的成分?分泌酶,一种酶所需的A?生产早老素还已知影响钙从内部储存的储存和释放。细胞内钙水平的变化是细胞内许多途径的关键信号,包括告诉神经元在激发动作电位时释放多少神经递质的信号。因此,早老素水平或功能的变化可能会影响突触传递通过改变或A?生产或细胞内钙水平。我们的长期目标是开发一个模型系统,使我们能够研究与AD相关的认知缺陷相关的突触功能障碍的分子和信号通路。我们将首先集中在PS1和APP。具体目标1的建议是确定野生型PS1在突触传递中的作用和测试的假设,即家族性AD连锁突变PS1的表达改变突触传递。具体目标2a是确定是否分泌A?42抑制兴奋性突触的传递,以及A240或半胱天冬酶抗切割突变体APPD 664 A是否可以减轻这种抑制。具体目标2b是确定烟碱乙酰胆碱受体、NMDA受体、I组代谢型谷氨酸受体和胰岛素受体在APP介导的突触传递抑制中的作用。我们的实验策略是使用电生理和光学成像技术,以确定特定的变化,在神经传递所产生的病毒介导的过度表达的野生型和突变形式的早老素,APP,APP裂解产物在培养的小鼠海马神经元。我们的实验室在研究病毒介导的多种蛋白质过表达对培养的海马神经元突触传递的影响方面有着丰富的经验,因此,我们处于一个很好的位置,可以利用这个系统来识别AD相关蛋白对神经传递的影响。这些研究将为新疗法提供分子靶点,以改善早期阿尔茨海默病患者的认知功能并延迟进一步的神经退行性变。阿尔茨海默病是老年人认知缺陷的最常见原因,并且被认为开始于突触功能障碍。了解这种突触功能障碍背后的细胞和分子机制将为治疗提供新的靶点,以缓解症状,减缓甚至阻止疾病进展。

项目成果

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JANE M SULLIVAN其他文献

JANE M SULLIVAN的其他文献

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{{ truncateString('JANE M SULLIVAN', 18)}}的其他基金

Reimbursement request for attending the Meeting of the Jointly Sponsored Institutional Predoctoral Training in the Neurosciences T32 Program Directors in Baltimore, MD on 2/19/19
参加 2019 年 2 月 19 日在马里兰州巴尔的摩联合主办的神经科学 T32 项目主任机构博士前培训会议的报销申请
  • 批准号:
    9898091
  • 财政年份:
    2019
  • 资助金额:
    $ 9.22万
  • 项目类别:
Graduate training in neuroscience
神经科学研究生培训
  • 批准号:
    9075995
  • 财政年份:
    2016
  • 资助金额:
    $ 9.22万
  • 项目类别:
Mechanisms of synapse dysfunction in Alzheimer's disease
阿尔茨海默病突触功能障碍的机制
  • 批准号:
    7996565
  • 财政年份:
    2007
  • 资助金额:
    $ 9.22万
  • 项目类别:
Mechanisms of synapse dysfunction in Alzheimer's disease
阿尔茨海默病突触功能障碍的机制
  • 批准号:
    7742186
  • 财政年份:
    2007
  • 资助金额:
    $ 9.22万
  • 项目类别:
Mechanisms of synapse dysfunction in Alzheimer's disease
阿尔茨海默病突触功能障碍的机制
  • 批准号:
    7367279
  • 财政年份:
    2007
  • 资助金额:
    $ 9.22万
  • 项目类别:
Mechanisms of synapse dysfunction in Alzheimer's disease
阿尔茨海默病突触功能障碍的机制
  • 批准号:
    7540888
  • 财政年份:
    2007
  • 资助金额:
    $ 9.22万
  • 项目类别:
CANNABINOID EFFECTS ON SYNAPTIC FUNCTION AND PLASTICITY
大麻素对突触功能和可塑性的影响
  • 批准号:
    2594615
  • 财政年份:
    1998
  • 资助金额:
    $ 9.22万
  • 项目类别:
CANNABINOID EFFECTS ON SYNAPTIC FUNCTION AND PLASTICITY
大麻素对突触功能和可塑性的影响
  • 批准号:
    6362843
  • 财政年份:
    1998
  • 资助金额:
    $ 9.22万
  • 项目类别:
CANNABINOID EFFECTS ON SYNAPTIC FUNCTION AND PLASTICITY
大麻素对突触功能和可塑性的影响
  • 批准号:
    2882640
  • 财政年份:
    1998
  • 资助金额:
    $ 9.22万
  • 项目类别:
CANNABINOID EFFECTS ON SYNAPTIC FUNCTION AND PLASTICITY
大麻素对突触功能和可塑性的影响
  • 批准号:
    6164478
  • 财政年份:
    1998
  • 资助金额:
    $ 9.22万
  • 项目类别:

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