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.

项目摘要 睡眠是支持认知功能的必不可少的生理行为。在阿尔茨海默氏病（AD）中 毁灭性神经退行性疾病，患者经历了加速的睡眠损失，可以相关 随着AD发作并有助于AD进展。 Tau是一种形成的轴突微管稳定蛋白 聚集体并促进了AD中的认知能力下降，突触丧失和神经元死亡。最近，tau 已被证明会在突触中进行错误的定位和聚集，这些突触可能会损害睡眠期间突触弱 - 可能负责形成睡眠的恢复益处。目前没有疗法来减轻 AD中TAU病理的负面后果。内源性大麻素为治疗提供了有趣的途径 干预是因为它们在促进抗炎性信号传导和睡眠中的作用。因此， 该建议是测试睡眠中断与TAU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，靶向内源性大麻素信号传导。我 假设睡眠破坏发生在AD进展早期，并且是随后的Tau的主要驱动力 错误定位和聚集以及认知能力下降。为了检验这一假设，我获得了P301S （PS19）过表达聚集的人tau。这些动物显示出年龄的依赖性 认知能力下降和tau积累。在AIM 1中，我将在6个月的PS19和WT动物中监视睡眠 将睡眠破坏的外观与TAU病理相关联，以连接睡眠中断和突触 tau病理学。此外，我将使小鼠通过零散的睡眠范式遭受慢性睡眠中断 将睡眠破坏与TAU病理相关。使用各种生化测定，我将确定睡眠依赖性 mRNA和蛋白质水平的变化。在AIM 2中，我将生成法庭 - / - /PS19小鼠并定义睡眠表型 在男性和女性中。我将确定突触ECB的遗传调节是否可以改善PS19的睡眠 小鼠并减少6个月时Tau病理。此外，我将测试遗传操纵的持久影响 通过一系列认知测试，ECB的睡眠数量和质量。突触睡眠依赖性变化将 可以通过生化测定法识别。这些研究将对行为有更深入的了解 AD中异常睡眠期间发生的分子变化，并突出显示内源性大麻素作为合适的 信号通路，以增强睡眠的恢复益处。该建议结合了行为， 生物化学，药理学和分子生物学，为我的科学提供出色的培训机会 生物医学科学领域的发展和未来职业。