Sleep-dependent synaptic homeostasis in Alzheimer's disease

阿尔茨海默病中睡眠依赖性突触稳态

• 批准号: 10209327
• 负责人: Todd Jonathan Cohen
• 金额: $ 210.65万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10209327
• 关键词: Acute; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid; Automobile Driving; Behavior; Behavior Therapy; Behavioral; Biological Markers; Biological Models; Brain; Chemicals; Cleaved cell; Cognition; Data; Defect; Development; Disease; Disease Progression; Early Diagnosis; Endocannabinoids; Etiology; Excision; Exposure to; Functional disorder; Genetic Models; Glutamate Receptor; Growth; Health; Hippocampus (Brain); Homeostasis; Human; Impaired cognition; Impairment; In Vitro; Individual; Intervention; Knockout Mice; Learning; Life; Link; Lipase; Maintenance; Measures; Mediating; Mediator of activation protein; Medicine; Memory; Metabotropic Glutamate Receptors; Modeling; Molecular; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Onset of illness; Pathologic; Pathology; Patients; Performance; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological Processes; Process; Prosencephalon; Protein Dephosphorylation; Publishing; Regulation; Risk; Senile Plaques; Signal Transduction; Sleep; Sleep Wake Cycle; Sleep disturbances; Source; Structure; Symptoms; Synapses; Synaptic plasticity; System; Tauopathies; Testing; Therapeutic; Treatment Efficacy; Variant; Work; age related; amyloid pathology; anandamide; base; brain health; cognitive function; endocannabinoid signaling; endogenous cannabinoid system; human disease; improved; in vitro Model; inhibitor/antagonist; insight; mouse model; neurotoxic; novel; predictive marker; sleep behavior; sleep quality; synaptic function; tau Proteins; tau aggregation; tau interaction; tau mutation; therapeutic evaluation; therapeutic target

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，对于大脑健康和维护至关重要 认知功能，例如学习和记忆。睡眠中断与衰老密切相关，并相信 暴露个人患阿尔茨海默氏病（AD）的风险。广告发作后，继续下降 睡眠量/质量与记忆表现和认知的逐步下降有关。所以， 睡眠破坏是脆弱性的来源，也是治疗疾病的潜在治疗靶标。详细的 分子对睡眠破坏的个体发育的理解可以有助于发展早期诊断 用于AD，并在识别基于睡眠药物的治疗窗口中。我们建议促进 在AD的早期阶段，优质的睡眠可能会延迟或停止进行性认知能力下降。但是， 支持认知的恢复过程的分子基础知之甚少。神经元 突触是负责形成和存储记忆的结构，尤其是在前脑结构中 例如海马和皮质。我们以前的工作表明，突触是 睡眠的恢复行为。我们已经表明，一种称为稳态缩放的突触可塑性形式 在睡眠期间参与大脑，以支持学习和记忆功能。突触功能障碍也是 已知在tau蛋白开始在大脑中积聚的时候，已知在AD进展的早期发生。我们 假设异常突触Tau通过改变稳态缩放来诱导突触功能障碍 向下，导致过度兴奋和睡眠破坏。睡眠中断和修复的损失 稳态缩放，然后加速疾病病理学和认知能力下降。初步发现表明 睡眠破坏是AD的基于TAU的小鼠模型中的早期表型。在AIM 1中，我们检查了互动 在Hallmark AD病理学，淀粉样蛋白斑块和Tau Tangles之间，驾驶睡眠中断并检查 在睡眠中断开始中Tau或淀粉样蛋白的必要性。我们测试睡眠中断之间的关系 和tau病理学，以建立睡眠破坏为病理的生物标志物。在AIM 2中，我们将使用体外 模型系统剖析致病性TAU蛋白会影响突触功能的分子机制。 我们将检查一种已知在AD人脑突触中积累的特定裂解的tau物种，并且 检查裂解的tau对恢复性稳态缩放缩小的影响。在AIM 3中，我们将检查 在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 数据表明，内源性大麻素信号在培养的神经元中的体内缩放缩放期间参与，并且 在AD模型小鼠中，在睡眠效益周期中的内源性大麻素调节被破坏。我们表明 使用药理方法急性增加内源性大麻素配胺可促进睡眠 有症状的AD小鼠。我们将在AD小鼠中测试这种促进睡眠策略的治疗功效 改变睡眠行为以改变人类患者的AD发作或进展的翻译意义。

项目成果

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: eNeuro
• 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

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: NEUROBIOLOGY OF STRESS
• 影响因子: 5
• 作者: Diering, Graham H.

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: Sleep
• 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