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

项目摘要 睡眠是一种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，患者经历加速失眠，这可能是相关的 阿尔茨海默病的发病，并有助于AD的进展。Tau是一种轴突微管稳定蛋白，形成 聚集并促成AD中的认知衰退、突触丢失和神经元死亡。最近，Tau 已被证明在突触中错位和聚集，这可能会削弱睡眠中突触的减弱 -可能对形成睡眠的恢复益处负责。目前还没有治疗方法来缓解 Tau病理在AD中的负面后果。内源性大麻素为治疗提供了一条有趣的途径 干预是因为它们在促进抗炎信号和睡眠方面的作用。因此，其目标是 这项提议是为了测试睡眠中断和tau聚集之间的联系，并测试治疗窗口 靶向睡眠中的内源性大麻素信号，在Tau病理和认知功能下降之前。我 假设睡眠中断发生在AD进展的早期，是随后tau的主要驱动因素 错误的本地化和聚合，以及认知能力下降。为了验证这一假设，我获得了P301S (PS19)过表达易于聚集的人Tau的转基因小鼠。这些动物表现出年龄依赖性 认知功能减退和Tau蓄积。在目标1中，我将监测6个月后PS19和WT动物的睡眠情况 将睡眠障碍的出现与Tau病理联系起来，以便将睡眠障碍与突触联系起来 陶氏病理学。此外，我将通过零碎的睡眠范例使小鼠遭受慢性睡眠干扰 将睡眠障碍与Tau病理联系起来。使用不同的生化分析，我将确定睡眠依赖 在信使核糖核酸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 在男性和女性身上。我将确定突触ECB的基因调控是否可以改善PS19的睡眠 并在6个月时减少tau病理改变。此外，我将测试基因操作的持久影响 ECB通过一系列认知测试对睡眠数量和质量进行了测试。突触睡眠依赖的变化将 通过生化检测进行鉴定。这些研究将提供对行为的更深入的理解 以及在AD患者睡眠异常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。这一提议结合了行为， 生物化学、药理学和分子生物学为我的科学提供了出色的培训机会 生物医学科学的发展和未来的职业生涯。

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.