Linking Sleep Dysfunction to Tau-related Degeneration across AD Progression

项目总结/摘要(来自家长奖) 在阿尔茨海默病患者中，睡眠和昼夜节律紊乱经常发生，甚至在认知能力下降之前就发生了。 阿尔茨海默病(AD)和其他神经退行性疾病--并构成住院的一个共同原因。 睡眠不足，特别是慢波睡眠(SWS)和睡眠碎片，可能通过以下方式导致AD 增加淀粉样β蛋白(Aβ)沉积，如PAR-18-497中所述，但Aβ单独似乎不足以 解释阿尔茨海默病临床表现和睡眠障碍的所有机制和原因。我们发现 人类睡眠和神经病理学研究中的汇聚证据表明，脑血管紧张素转换酶在睡眠中起主要的、新的作用 阿尔茨海默病中的牵张症--睡眠障碍。在这方面，在AD受试者的死后大脑中，皮质下核团 参与睡眠-觉醒调节的人是最早发展出基于tau的AD类型神经纤维的人之一 β斑块出现前的纠缠。我们的工作假设是tau诱导的皮质下变性 控制1)SWS的核团；2)清醒-唤醒；3)昼夜节律是导致睡眠中断的早期因素- 阿尔茨海默病中的觉醒行为，先于认知衰退和后来出现的睡眠前馈周期 扰动和加速A-β沉积。我们建议测试睡眠-觉醒行为的差异是否在 进展性AD分期与健康对照组与PSP(一种皮质下更明显的单纯肌萎缩症) 面积)是由定量病理解剖措施的差异(包括总数和 参与觉醒和NREM睡眠调节的核团中的特定神经元数量和hp-tau负荷)。 我们独一无二地准备成功，因为我们可以接触到AD和PSP患者的大型纵向队列以及 年龄相近的对照组和成功的尸检计划，p-tau和A-βPET成像方面的专业知识，深度 神经退行性疾病的临床睡眠研究经验，老年对照组织收集，病例 涵盖所有AD谱和其他tauopathy，实现全脑区域、体验的立体 在人类皮质下病理解剖学，以及前沿的神经病理学方法和脑网络方法。 这一因素的组合创造了一个独特的机会，可以利用新的人类发现来提供信息和 补充机械假设和模型系统中的测试。这一点很关键，因为动物的睡眠- 尾流模式和类似AD的模型与人类的模型不同，实验模型更像是非 而不是与tau相关的AD模式。我们预计我们的发现将为关于 睡眠和/或昼夜节律被打乱的时间序列和蛋白质的积累和传播 AD中的聚集体，如p-t和Aβ。除此之外，这项研究的结果将为合理的治疗提供参考 治疗阿尔茨海默病患者睡眠障碍。

PROJECT SUMMARY / ABSTRACT (from parent award) Sleep and circadian disturbances occur often and even precede the onset of cognitive decline, in Alzheimer' disease (AD) and other neurodegenerative diseases – and constitute a common reason for institutionalization. Sleep loss, particulary slow wave sleep (SWS), and sleep fragmentation, may contribute causally to AD by increasing amyloid-beta (Aβ) deposition, as described in PAR-18-497, but Aβ alone appears insufficient to explain all mechanisms and causation of AD clinical manifestations and disordered sleep. We discovered converging evidence in human sleep and neuropathological studies suggestive of a primary, novel role of tauopathy in AD-disordered sleep. In this connection, in postmortem brains of AD subjects, subcortical nuclei involved in circandian-sleep- -wake regulation are among the first to develop AD-type tau-based neurofibrillary tangles, before Aβ plaques appear. Our working hypothesis is that tau-induced degeneration of subcortical nuclei controlling 1) SWS; 2) waking-arousal; and 3) circadian timing is an early contributor to disrupted sleep- wake behavior in AD, preceding both cognitive decline and later emergence of the feedforward cycle of sleep disturbance and accelerated Aβ deposition. We propose to test if differences in sleep-wake behavior in progressive AD stages versus healthy controls vs. PSP ( a pure tauopathy more pronounced in subcortical areas) are accounted by differences in quantitative pathoanatomical measures (including numbers of total and specific neuronal population, and hp-tau burden) in nuclei involved in wake and NREM sleep regulation. We are uniquely poised to suceed due to our access to large longitudinal cohorts of AD and PSP patients and similarly-aged controls and successful autopsy program, expertise in p-tau and Aβ PET imaging, deep experience in clinical sleep studies in neurodegenerative disorders, tissue collections of aged controls, cases encompassing all-AD spectrum and other tauopathies, enabling stereology of whole brain regions, experience in human subcortical pathoanatomy, and cutting-edge neuropathological methods and brain network approach. This combination of factors create 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 p-t and Aβ in AD. Beyond this, results from this study will inform rational therapies for treating disturbed sleep in AD.