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

项目摘要 睡眠是支持认知功能的基本生理行为。在阿尔茨海默病（AD）中， 毁灭性的神经退行性疾病，患者经历加速的睡眠丧失，这可能与 与AD发病相关，并促进AD进展。Tau是一种轴突微管稳定蛋白， 聚集并促成AD中所见的认知下降、突触丧失和神经元死亡。最近，Tau 已被证明在突触中错误定位和聚集，这可能在睡眠期间损害突触弱化 - 这可能是形成睡眠的恢复益处的原因。目前还没有治疗方法来缓解 AD中tau病理学的负面后果。内源性大麻素提供了一种有趣的治疗途径， 因为它们在促进抗炎信号传导和睡眠中的作用。因此， 这一建议是为了测试睡眠中断和tau蛋白聚集之间的联系 靶向内源性大麻素信号在睡眠中提前Tau病理和认知能力下降。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。为了验证这一假设，我获得了P301 S （PS19）转基因小鼠，其过表达易聚集的人Tau。这些动物表现出年龄依赖性 认知能力下降和Tau积累。在目标1中，我将监测6个月PS19和WT动物的睡眠， 将睡眠中断的出现与Tau病理学相关联，以便将睡眠中断和突触 Tau病理学此外，我将通过一种碎片化的睡眠模式使小鼠长期睡眠中断， 睡眠中断与Tau病理学有关利用各种生化分析，我将找出睡眠依赖性 mRNA和蛋白质水平的变化。在目标2中，我将产生FAAH-/-/PS19小鼠并定义睡眠表型 在男性和女性。我将确定突触eCB的遗传调节是否可以改善PS19中的睡眠 在6个月时，小鼠和减少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对睡眠数量和质量的影响。突触睡眠依赖性变化 通过生物化学分析鉴定。这些研究将提供一个更深入的了解行为 以及AD患者异常睡眠期间发生的分子变化，并强调内源性大麻素是一种合适的 增强睡眠恢复益处的信号通路。这个提议结合了行为， 生物化学，药理学和分子生物学提供优秀的培训机会，我的科学 生物医学科学的发展和未来职业。

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.