Sleep-dependent synaptic homeostasis in Alzheimer's disease

阿尔茨海默病中睡眠依赖性突触稳态

基本信息

  • 批准号:
    10209327
  • 负责人:
  • 金额:
    $ 210.65万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-04-15 至 2024-03-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Sleep is an essential conserved behavior seen throughout life and is critical for brain health and maintenance of cognitive functions such as learning and memory. Sleep disruption is intimately linked to aging and believed to expose individuals to risk of developing Alzheimer's Disease (AD). After AD onset, continued decline in sleep amount/quality is associated with progressive decline in memory performance and cognition. Therefore, sleep disruption is a source of vulnerability as well as a potential therapeutic target to treat disease. A detailed molecular understanding of the ontogeny of sleep disruption could aid in the development of earlier diagnosis for AD, and in the identification of a therapeutic window for sleep-based medicines. We propose that promoting quality sleep during the early stages of AD may delay or halt progressive cognitive decline. However, the molecular basis of sleep's restorative processes that support cognition is poorly understood. Neuronal synapses are the structures responsible for forming and storing memories, particularly in forebrain structures such as the hippocampus and cortex. Our previous work shows that synapses are a major target for the restorative actions of sleep. We have shown that a form of synaptic plasticity called homeostatic scaling-down is engaged in the brain during sleep to support learning and memory functions. Synapse dysfunction is also known to occur early in AD progression when the Tau protein begins to accumulate in the brain. We hypothesize that aberrant synaptic Tau induces synaptic dysfunction by altering homeostatic scaling- down, leading to hyperexcitability and sleep disruption. Sleep disruption, and loss of the restorative homeostatic scaling, then accelerates disease pathology and cognitive decline. Preliminary findings indicate sleep disruption is an early phenotype in a Tau-based mouse model of AD. In aim 1 we examine the interaction between hallmark AD pathologies, amyloid plaques and Tau tangles, in driving sleep disruption, and examine the necessity of Tau or amyloid in sleep disruption onset. We test the relationship between sleep disruption and Tau pathology to establish sleep disruption as a biomarkers of pathology. In aim 2 we will use an in vitro model system to dissect the molecular mechanisms by which pathogenic Tau proteins affect synapse function. We will examine a particular cleaved Tau species known to accumulate at the synapse in AD human brain, and examine the effect of cleaved Tau on restorative homeostatic scaling-down. In aim 3 we will examine the sleep-dependent regulation of the endocannabinoid system during aging in AD model mice. Our preliminary data show that endocannabinoid signaling is engaged during homeostatic scaling in cultured neurons, and that regulation of endocannabinoids during the sleep-wake cycle is disrupted in AD model mice. We show that acutely increasing the endocannabinoid anandamide using a pharmacological approach promotes sleep in symptomatic AD mice. We will test the therapeutic efficacy of this sleep-promoting strategy in AD mice, with the translational implications of modifying sleep behavior to alter AD onset or progression in human patients.
项目摘要 睡眠是一生中必不可少的保守行为,对大脑健康和维护至关重要 学习和记忆等认知功能。睡眠中断与衰老密切相关, 使个体暴露于患阿尔茨海默病(AD)的风险。AD发作后, 睡眠量/质量与记忆表现和认知的进行性下降有关。因此,我们认为, 睡眠中断是脆弱性来源,也是治疗疾病的潜在治疗靶点。详细 对睡眠中断个体发生的分子理解有助于早期诊断的发展 用于AD,并用于识别基于睡眠的药物的治疗窗口。我们建议, 在AD的早期阶段,高质量的睡眠可能会延迟或停止进行性认知能力下降。但 支持认知的睡眠恢复过程的分子基础知之甚少。神经元 突触是负责形成和储存记忆的结构,特别是在前脑结构中 比如海马体和皮层。我们以前的工作表明,突触是一个主要的目标, 睡眠的恢复作用。我们已经证明了一种叫做稳态缩小的突触可塑性 在睡眠期间参与大脑,以支持学习和记忆功能。突触功能障碍 已知在AD进展的早期发生,此时Tau蛋白开始在脑中积累。我们 假设异常突触Tau通过改变稳态比例来诱导突触功能障碍- 导致过度兴奋和睡眠中断。睡眠中断,以及恢复性的 内稳态缩放,然后加速疾病病理和认知能力下降。初步调查结果显示 睡眠中断是基于Tau AD小鼠模型中的早期表型。在目标1中,我们研究了 之间的标志性AD病理,淀粉样蛋白斑块和Tau缠结,在驾驶睡眠中断,并检查 Tau蛋白或淀粉样蛋白在睡眠中断发作中的必要性。我们测试了睡眠中断 和Tau病理学来建立睡眠中断作为病理学的生物标志物。在目标2中,我们将使用体外 模型系统来剖析致病性Tau蛋白影响突触功能的分子机制。 我们将检查已知在AD人脑中的突触处积累的特定切割的Tau种类, 检查切割的Tau对恢复性稳态按比例缩小的影响。在目标3中,我们将研究 AD模型小鼠衰老过程中内源性大麻素系统的睡眠依赖性调节。我们的初步 数据显示,内源性大麻素信号传导在培养的神经元中的稳态缩放期间参与,并且 在AD模型小鼠中,睡眠-觉醒周期期间内源性大麻素的调节被破坏。我们证明了 使用药理学方法急剧增加内源性大麻素anandamide促进睡眠, 症状性AD小鼠。我们将测试这种睡眠促进策略在AD小鼠中的治疗效果, 在人类患者中改变睡眠行为以改变AD发作或进展的翻译意义。

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Coordinated Regulation of CB1 Cannabinoid Receptors and Anandamide Metabolism Stabilizes Network Activity during Homeostatic Downscaling.
CB1 大麻素受体和 Anandamide 代谢的协调调节可稳定稳态降尺度期间的网络活动。
  • DOI:
    10.1523/eneuro.0276-22.2022
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    3.4
  • 作者:
    Ye,Michael;Monroe,SarahK;Gay,SeanM;Armstrong,MichaelL;Youngstrom,DianeE;Urbina,FabioL;Gupton,StephanieL;Reisdorph,Nichole;Diering,GrahamH
  • 通讯作者:
    Diering,GrahamH
Tonic endocannabinoid signaling supports sleep through development in both sexes.
补品内源性大麻素信号传导通过两性的发育来支持睡眠。
  • DOI:
    10.1093/sleep/zsac083
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    5.6
  • 作者:
    Martin,ShenéeC;Gay,SeanM;Armstrong,MichaelL;Pazhayam,NilaM;Reisdorph,Nichole;Diering,GrahamH
  • 通讯作者:
    Diering,GrahamH
Remembering and forgetting in sleep: Selective synaptic plasticity during sleep driven by scaling factors Homer1a and Arc.
  • DOI:
    10.1016/j.ynstr.2022.100512
  • 发表时间:
    2023-01
  • 期刊:
  • 影响因子:
    5
  • 作者:
    Diering, Graham H.
  • 通讯作者:
    Diering, Graham H.
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Todd Jonathan Cohen其他文献

Todd Jonathan Cohen的其他文献

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{{ truncateString('Todd Jonathan Cohen', 18)}}的其他基金

Identifying kinase signaling pathways linked to tau-mediated neurodegeneration
识别与 tau 介导的神经变性相关的激酶信号通路
  • 批准号:
    10753257
  • 财政年份:
    2023
  • 资助金额:
    $ 210.65万
  • 项目类别:
CRISPR gene therapies targeting tau in Alzheimer's disease and tauopathies
针对阿尔茨海默病和 tau 病中 tau 蛋白的 CRISPR 基因疗法
  • 批准号:
    10752745
  • 财政年份:
    2023
  • 资助金额:
    $ 210.65万
  • 项目类别:
Identifying Alzheimer’s Disease Causal Variants and Target Genes Using iPSC-derived Microglia
使用 iPSC 衍生的小胶质细胞识别阿尔茨海默病致病变异和靶基因
  • 批准号:
    10382389
  • 财政年份:
    2020
  • 资助金额:
    $ 210.65万
  • 项目类别:
Identifying Alzheimer’s Disease Causal Variants and Target Genes Using iPSC-derived Microglia
使用 iPSC 衍生的小胶质细胞识别阿尔茨海默病致病变异和靶基因
  • 批准号:
    10615602
  • 财政年份:
    2020
  • 资助金额:
    $ 210.65万
  • 项目类别:
Dual CHIP Functions Control Tau Triage In Alzheimer's Disease
双芯片功能控制阿尔茨海默氏病的 Tau 分类
  • 批准号:
    10088361
  • 财政年份:
    2019
  • 资助金额:
    $ 210.65万
  • 项目类别:
Dual CHIP Functions Control Tau Triage In Alzheimer's Disease
双芯片功能控制阿尔茨海默氏病的 Tau 分类
  • 批准号:
    10319914
  • 财政年份:
    2019
  • 资助金额:
    $ 210.65万
  • 项目类别:
Dual CHIP Functions Control Tau Triage In Alzheimer's Disease
双芯片功能控制阿尔茨海默氏病的 Tau 分类
  • 批准号:
    10539271
  • 财政年份:
    2019
  • 资助金额:
    $ 210.65万
  • 项目类别:
Elucidating The Aberrant TDP-43 Species That Promote Neurodegeneration
阐明促进神经退行性变的异常 TDP-43 物种
  • 批准号:
    10385722
  • 财政年份:
    2018
  • 资助金额:
    $ 210.65万
  • 项目类别:
TDP-43 acetylation as a pathogenic modification in ALS & related proteinopathies
TDP-43 乙酰化作为 ALS 的致病修饰
  • 批准号:
    8849550
  • 财政年份:
    2014
  • 资助金额:
    $ 210.65万
  • 项目类别:
TDP-43 acetylation as a pathogenic modification in ALS & related proteinopathies
TDP-43 乙酰化作为 ALS 的致病修饰
  • 批准号:
    8862550
  • 财政年份:
    2014
  • 资助金额:
    $ 210.65万
  • 项目类别:

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Hormone therapy, age of menopause, previous parity, and APOE genotype affect cognition in aging humans.
激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
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