Sleep-dependent synaptic homeostasis in Alzheimer's disease

项目总结 睡眠是一种终生可见的基本保守行为，对大脑健康和维护至关重要 认知功能，如学习和记忆。睡眠障碍与衰老密切相关，人们认为 使个人面临罹患阿尔茨海默病(AD)的风险。AD发病后， 睡眠数量/质量与记忆性能和认知能力的进行性下降有关。因此， 睡眠障碍是脆弱的一个来源，也是治疗疾病的潜在治疗目标。一个详细的 对睡眠障碍个体发生的分子理解有助于发展早期诊断 对于阿尔茨海默病，以及在确定睡眠药物的治疗窗口方面。我们建议推广 阿尔茨海默病早期的高质量睡眠可能会延缓或阻止进行性认知能力下降。然而， 支持认知的睡眠恢复过程的分子基础还知之甚少。神经元 突触是负责形成和存储记忆的结构，尤其是在前脑结构中 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形式的突触可塑性，称为内稳态缩小 在睡眠期间参与大脑，以支持学习和记忆功能。突触功能障碍也是 已知发生在AD进展的早期，当Tau蛋白开始在大脑中积累时。我们 假设异常突触Tau通过改变内环境平衡比例而导致突触功能障碍- 会导致过度兴奋和睡眠中断。睡眠中断，失去恢复能力 动态平衡的伸缩，然后加速疾病病理和认知能力下降。初步调查结果表明 睡眠障碍是以Tau为基础的AD小鼠模型的早期表型。在目标1中，我们检查相互作用 在标志性AD病理、淀粉样斑块和Tau缠结之间，在驱动睡眠障碍方面，并检查 牛磺酸或淀粉样蛋白在睡眠障碍发病中的必要性。我们测试了睡眠中断之间的关系 并将Tau病理确立为睡眠障碍的病理生物标志物。在目标2中，我们将使用体外培养的 模型系统，剖析致病Tau蛋白影响突触功能的分子机制。 我们将研究一种特定的被切割的Tau物种，这种物种已知积累在AD人类大脑的突触处，并且 检查裂解Tau对恢复性内环境平衡缩小的影响。在目标3中，我们将研究 阿尔茨海默病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。我们的预赛 数据显示，在培养的神经元中，内源性大麻素信号参与了动态平衡调节，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打乱。我们证明了 用药理学方法急剧增加内源性大麻素脱氢表雄胺促进睡眠 症状阿尔茨海默病小鼠。我们将在AD小鼠身上测试这种促进睡眠的策略的治疗效果， 改变睡眠行为以改变人类患者AD发病或进展的翻译含义。

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.