Linking Sleep Dysfunction to Tau-related Degeneration across AD Progression

项目摘要/摘要 觉醒、睡眠和昼夜节律紊乱是阿尔茨海默病(AD)的常见症状，经常出现 先前的遗忘症症状。这种干扰影响了患者和照顾者的生活质量， 推进制度化。淀粉样β蛋白(A-β)沉积与睡眠障碍的双向相关性 导致慢波睡眠(SWS)不足和睡眠碎片化。我们发现了证据集中在 人类睡眠和神经病理学研究表明，进行性核上性瘫痪患者 (PSP)是一种主要的牵张症，表现为睡眠时间短得多的极端睡眠表型。这 与β无关的tau相关退行性变作为睡眠功能障碍的潜在原因的作用 证词。有趣的是，脑干、下丘脑和基底前脑核团参与脑干-睡眠-觉醒 调节形成基于AD-tau的神经原纤维缠结在皮质区域缠结之前，通常在 出现β斑块。我们的工作假设是tau诱导关键脑干、下丘脑的变性 基底前脑核团控制1)SWS；2)清醒-唤醒；3)睡眠-觉醒的昼夜节律 阿尔茨海默病中的行为，先于认知能力下降和后来出现的睡眠前馈周期 扰动和加速A-β沉积。我们将通过对比睡眠-觉醒行为来测试我们的假设 通过分析客观睡眠测量的差异，对进展性AD分期与健康对照组进行比较， 临床和分子影像特征及尾波相关核团的定量病理解剖测量， NREM睡眠调节与昼夜节律。另外，增加PSP作为阳性对照组。 由于我们的团队专业知识、合作的记录和我们的 获得独一无二的、特征明确的临床病理队列。这一因素的组合创造了一个独特的 利用新的人类发现的机会，这些发现将提供信息并补充机械论假说和 在模型系统中进行测试。这一点至关重要，因为动物的睡眠-觉醒模式和类似AD的模型是不同的 与人类和实验模型相比，更像是非AD的tauopathy而不是tau相关的AD 模式。我们预计，我们的发现将为睡眠中断的时间序列提供关键信息 和/或昼夜节律以及蛋白质聚集体的积累和扩散，如磷酸-tau和 公元后的Aβ。除此之外，这项研究的结果将为治疗阿尔茨海默病睡眠障碍提供合理的治疗方案。

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.