Linking Sleep Dysfunction to Tau-related Degeneration across AD Progression

项目总结/摘要 觉醒、睡眠和昼夜节律紊乱是阿尔茨海默病（AD）的常见现象， 之前的遗忘症状这种干扰影响患者和护理人员的生活质量， 推进制度化建设。β淀粉样蛋白（Aβ）沉积与睡眠障碍之间的双向相关性 导致慢波睡眠（SWS）缺陷和睡眠碎片。我们发现了一些证据 人类睡眠和神经病理学研究表明， (PSP)原发性tau蛋白病表现出极端睡眠表型，其特征是睡眠持续时间短得多。这 点tau蛋白相关变性作为睡眠障碍的潜在原因，独立于Aβ 证词有趣的是，脑干、下丘脑和基底前脑核团参与了昼夜节律-睡眠-觉醒， 调节在皮质区缠结之前发展基于AD-tau的神经元缠结，并且通常在皮质区缠结之前， 出现Aβ斑块。我们的工作假设是tau诱导的关键脑干，下丘脑， 和基底前脑核团控制1）SWS; 2）觉醒;和3）昼夜节律的时间基础睡眠-觉醒 行为，在认知下降和后来出现的前馈周期的睡眠 干扰和加速Aβ沉积。我们将测试我们的假设对比睡眠和觉醒行为， 通过分析客观睡眠测量的差异， 临床和分子成像概况以及涉及唤醒的核团中的定量病理解剖学测量， NREM睡眠调节和昼夜节律。此外，我们将添加PSP作为阳性对照组。 由于我们的团队专业知识、合作记录以及我们的 获得独特的良好表征的临床病理学队列。这些因素的结合创造了一个独特的 有机会利用新的人类发现，将告知和补充机械假说， 在模型系统中进行测试。这一点至关重要，因为动物的睡眠-觉醒模式和类AD模型存在差异 与人类和实验模型相比， 模式.我们预计我们的发现将为睡眠中断的时间顺序提供关键信息 和/或昼夜节律以及蛋白质聚集体如磷酸化-tau和 AD中的Aβ。除此之外，这项研究的结果将为治疗AD睡眠障碍的合理疗法提供信息。

PROJECT SUMMARY / ABSTRACT Wake, sleep and circadian disturbances are common occurrences in Alzheimer' disease (AD), often times preceding amnestic symptoms. Such disturbances affect the quality of life of patients and caregivers alike and boost institutionalization. A bidirectional correlation between amyloid-beta (Aβ) deposition and disturbed sleep contributes to slow wave sleep (SWS) deficits and sleep fragmentation. We discovered converging evidence in human sleep and neuropathological studies suggesting that individuals with progressive supranuclear palsy (PSP), a primary tauopathy, show an extreme sleep phenotype featuring a much shorter sleep duration. This point for a role of tau-related degeneration as an underlying cause of sleep disfunction, independent of Aβ deposition. Interestingly, brainstem, hypothalamic and basal forebrain nuclei involved in circandian-sleep-wake regulation develop AD- tau-based neurofibrillary tangles preceding tangles in cortical areas and often, before Aβ plaques appear. Our working hypothesis is that tau-induced degeneration of key brainstem, hypothalamic and basal forebrain nuclei controlling 1) SWS; 2) waking-arousal; and 3) circadian timing underlie sleep-wake behavior in AD, preceding both cognitive decline and later emergence of the feedforward cycle of sleep disturbance and accelerated Aβ deposition. We will test our hypothesis contrasting sleep-wake behavior in progressive AD stages versus healthy controls by analyzing differences in objective sleep measurements, clinical and molecular imaging profiles and quantitative pathoanatomical measures in nuclei involved in wake, NREM sleep regulation and circadian rhythm. Moreover, we will add a PSP as a positive control group. We are uniquely poised to succeed due to our group expertise, track record of working together and our access to uniquely well characterized clinicopathological cohort. This combination of factors creates a unique opportunity to exploit novel human findings that will inform and complement mechanistic hypotheses and testing in model systems. This is critical because animals' sleep-wake patterns and AD-like models diverge from those of humans and experimental models rather mimic non-AD tauopathies than tau-related AD patterns. We anticipate our findings will inform critical information on the temporal sequence of disrupted sleep and/or circadian rhythms and the accumulation and spreading of protein aggregates such as phospho-tau and Aβ in AD. Beyond this, results from this study will inform rational therapies for treating disturbed sleep in AD.