Sleep disruption in the progression and treatment of Alzheimer's disease

阿尔茨海默病的进展和治疗中的睡眠中断

• 批准号: 10474344
• 负责人: Shenee Martin
• 金额: $ 3.36万
• 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: 2021-08-03 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474344
• 关键词: Acute; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Animals; Anti-Inflammatory Agents; Appearance; Axon; Behavior; Behavioral; Biochemical; Biochemistry; Biological Assay; Brain; Chronic; Cognitive; Custom; Data; Deterioration; Development; Diagnosis; Disease; Disease Progression; Endocannabinoids; Ensure; Enzymes; Excessive Daytime Sleepiness; Female; Fractionation; Future; Genetic; Hippocampus (Brain); Human; Impaired cognition; Impairment; Individual; Inflammation; Institutionalization; Lead; Link; Lipase; Measures; Messenger RNA; Microtubule Stabilization; Molecular; Molecular Biology; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurotransmitters; Onset of illness; Pathology; Patients; Persons; Pharmacology; Phenotype; Physiological; Polysomnography; Population; Prevalence; Proteins; Regulation; Role; Science; Signal Pathway; Signal Transduction; Sleep; Sleep Deprivation; Sleep disturbances; Sleeplessness; Synapses; Synaptic Transmission; Testing; Therapeutic; Therapeutic Intervention; Training; Transgenic Mice; Western Blotting; age related; behavior test; cannabinoid receptor; career; cognitive function; cognitive testing; endocannabinoid signaling; endogenous cannabinoid system; excitotoxicity; expectation; experience; genetic manipulation; improved; mRNA Expression; male; mouse model; neuron loss; overexpression; prevent; sleep abnormalities; sleep behavior; sleep quality; sleep quantity; tau Proteins; tau aggregation; tau-1; therapeutic evaluation; therapeutic target; therapy design/development; training opportunity

Project Summary Sleep is an essential physiological behavior that supports cognitive function. In Alzheimer's disease (AD), a devastating neurodegenerative disorder, patients experience accelerated sleep loss which can be correlated with AD onset and contribute to AD progression. Tau is an axonal microtubule stabilizing protein that forms aggregates and contributes to the cognitive decline, synapse loss and neuronal death seen in AD. Recently, Tau has been shown to mislocalize and aggregate in synapses which may impair synapse weakening during sleep – likely responsible for forming the restorative benefits of sleep. Currently there are no therapies to alleviate the negative consequences of tau pathology in AD. Endocannabinoids provide an intriguing avenue for therapeutic intervention because of their role in promoting antinflammatory signaling and sleep. Therefore, the objectives of this proposal are to test the link between sleep disruption and tau aggregation and to test the therapeutic window targeting endocannabinoid signaling during sleep in advance of Tau pathology and cognitive decline. I hypothesize that sleep disruption occurs early in AD progression and is a major driver of subsequent tau mislocalization and aggregation, and cognitive decline. In order to test this hypothesis, I have obtained P301S (PS19) transgenic mice that overexpress aggregation-prone human Tau. These animals show age-dependent cognitive decline and Tau accumulation. In Aim 1, I will monitor sleep in 6 months PS19 and WT animals and correlate the appearance of sleep disruption with Tau pathology, in order to link sleep disruption and synaptic Tau pathology. Additionally, I will subject mice to chronic sleep disruption via a fragmented sleep paradigm to correlate sleep disruption with Tau pathology. Using various biochemical assays, I will identify sleep-dependent changes at the mRNA and protein level. In Aim 2 I will generate FAAH-/-/PS19 mice and define sleep phenotypes in males and females. I will determine whether genetic regulation of synaptic eCBs can improve sleep in PS19 mice and reduce tau pathology at 6 months. Additionally, I will test the lasting effects of genetic manipulation of eCBs on sleep quantity and quality through a battery of cognitive tests. Synaptic sleep-dependent changes will be identified through biochemical assays. These studies will provide a deeper understanding of the behavioral and molecular changes that occur during abnormal sleep in AD and highlight endocannabinoids as a suitable signaling pathway for enhancing the restorative benefits of sleep. This proposal combines behavior, biochemistry, pharmacology and molecular biology to provide outstanding training opportunities for my scientific development and future career in biomedical science.

项目概要 睡眠是支持认知功能的重要生理行为。在阿尔茨海默病 (AD) 中， 毁灭性的神经退行性疾病，患者会经历加速的睡眠丧失，这可能与 与 AD 发病有关并促进 AD 进展。 Tau 是一种轴突微管稳定蛋白，形成 聚集并导致 AD 中出现的认知能力下降、突触丧失和神经元死亡。最近，陶 已被证明会在突触中错误定位和聚集，这可能会损害睡眠期间的突触减弱 – 可能负责形成睡眠的恢复功效。目前尚无缓解该症状的治疗方法 AD 中 tau 蛋白病理学的负面影响。内源性大麻素为治疗提供了一条有趣的途径 干预，因为它们在促进抗炎信号传导和睡眠方面的作用。因此，目标 该提案旨在测试睡眠中断与 tau 蛋白聚集之间的联系并测试治疗窗口 在 Tau 病理学和认知能力下降之前，针对睡眠期间的内源性大麻素信号传导。我 假设睡眠中断发生在 AD 进展的早期，并且是随后 tau 蛋白的主要驱动因素 错误定位和聚集以及认知能力下降。为了验证这个假设，我获得了P301S (PS19) 转基因小鼠过度表达易于聚集的人类 Tau。这些动物表现出年龄依赖性 认知能力下降和 Tau 蛋白积累。在目标 1 中，我将监测 PS19 和 WT 动物 6 个月的睡眠情况， 将睡眠中断的出现与 Tau 病理学相关联，以便将睡眠中断与突触联系起来 Tau 病理学。此外，我将通过碎片化睡眠范式让小鼠遭受慢性睡眠干扰，以 将睡眠中断与 Tau 病理学联系起来。使用各种生化检测，我将识别睡眠依赖性 mRNA 和蛋白质水平发生变化。在目标 2 中，我将生成 FAAH-/-/PS19 小鼠并定义睡眠表型 在男性和女性中。我将确定突触 eCB 的基因调控是否可以改善 PS19 的睡眠 小鼠并在 6 个月时减少 tau 病理学。此外，我将测试基因操纵的持久影响 eCB 通过一系列认知测试来评估睡眠数量和质量。突触睡眠依赖性变化将 通过生化分析来鉴定。这些研究将提供对行为的更深入的了解 以及 AD 异常睡眠期间发生的分子变化，并强调内源性大麻素作为合适的药物 增强睡眠恢复功效的信号通路。该提案结合了行为， 生物化学、药理学和分子生物学为我的科学研究提供了良好的培训机会 生物医学科学的发展和未来职业。