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.

项目概要 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 学习和记忆等认知功能。睡眠中断与衰老密切相关，人们相信 使个人面临患阿尔茨海默病 (AD) 的风险。 AD发病后，持续下降 睡眠量/质量与记忆力和认知能力的逐渐下降有关。所以， 睡眠中断是脆弱性的根源，也是治疗疾病的潜在治疗目标。详细的 对睡眠中断个体发育的分子理解可能有助于早期诊断的发展 AD，以及确定基于睡眠的药物的治疗窗口。我们建议提倡 AD 早期阶段的优质睡眠可能会延缓或阻止进行性认知能力下降。然而， 人们对支持认知的睡眠恢复过程的分子基础知之甚少。神经元 突触是负责形成和存储记忆的结构，特别是在前脑结构中 例如海马体和皮质。我们之前的工作表明突触是 睡眠的恢复作用。我们已经证明了一种称为稳态缩小的突触可塑性形式 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 已知发生在 AD 进展早期，此时 Tau 蛋白开始在大脑中积聚。我们 假设异常的突触 Tau 通过改变稳态尺度来诱导突触功能障碍 下降，导致过度兴奋和睡眠中断。睡眠中断，恢复力丧失 稳态缩放，然后加速疾病病理和认知能力下降。初步调查结果表明 睡眠中断是基于 Tau 的 AD 小鼠模型的早期表型。在目标 1 中，我们检查交互作用 标志性 AD 病理、淀粉样斑块和 Tau 蛋白缠结之间在驱动睡眠中断方面的作用，并检查 Tau 蛋白或淀粉样蛋白在睡眠中断发生中的必要性。我们测试睡眠中断之间的关系 和 Tau 病理学将睡眠中断确立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 人类大脑突触处积累的特定切割 Tau 蛋白物种，并且 检查切割的 Tau 对恢复性稳态缩小的影响。在目标 3 中，我们将检查 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神经元的稳态缩放过程中起作用，并且 在AD模型小鼠中，睡眠-觉醒周期中内源性大麻素的调节被破坏。我们表明 使用药理学方法急剧增加内源性大麻素 anandamide 可促进睡眠 有症状的 AD 小鼠。我们将测试这种促进睡眠策略对 AD 小鼠的治疗效果， 改变睡眠行为以改变人类患者 AD 发病或进展的转化意义。

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

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

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.