Linking Sleep Dysfunction to Tau-related Degeneration across AD Progression

将睡眠功能障碍与 AD 进展过程中 Tau 蛋白相关的退化联系起来

• 批准号: 10328419
• 负责人: Lea Tenenholz Grinberg
• 金额: $ 1.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328419
• 关键词: Alzheimer' s Disease; Alzheimer' s disease brain; Amyloid beta-Protein; Animals; Area; Arousal; Autopsy; Award; Behavior; Biological Models; Brain; Brain region; Cell Nucleus; Circadian Dysregulation; Circadian Rhythms; Clinical; Complement; Disease Progression; Etiology; Experimental Models; Human; Impaired cognition; Institutionalization; Link; Longitudinal cohort; Measures; Methods; Modeling; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Parents; Patients; Pattern; Population; Positron-Emission Tomography; Regulation; Role; Senile Plaques; Sleep; Sleep Deprivation; Sleep Disorders; Sleep Fragmentations; Sleep disturbances; Slow-Wave Sleep; Suggestion; Tauopathies; Testing; Tissue Banks; abeta deposition; aged; base; brain cell; circadian; cohort; experience; human model; non rapid eye movement; novel; programs; protein aggregation; sleep regulation; tau Proteins; tau-1

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.

项目摘要 /摘要（来自父母奖） 在阿尔茨海默氏症中，睡眠和昼夜节律障碍经常发生，甚至是认知能力下降的发作。 疾病（AD）和其他神经退行性疾病 - 构成了制度化的共同原因。 睡眠损失，特定的慢波睡眠（SWS）和睡眠破碎，不幸的是 如Par-18-497所述，增加淀粉样蛋白β（Aβ）沉积，但仅Aβ似乎不足 解释AD临床表现和睡眠不足的所有机制和原因。我们发现了 人类睡眠和神经病理学研究的融合证据表明，主要的新作用 在广告中的睡眠中的tauopathy。在这方面，在AD受试者的后大脑中，皮层核 涉及大型滑脚的调节是最早开发基于AD型Tau的神经原纤维的人之一 在出现Aβ斑块之前缠结。我们的工作假设是tau诱导的皮层变性 核控制1）SWS； 2）醒来； 3）昼夜节律是造成睡眠干扰的早期贡献者 - AD中的唤醒行为，在认知能力下降和后来的睡眠周期的出现之前 干扰和加速Aβ沉积。我们建议测试睡眠效果行为的差异 渐进式广告阶段与健康对照与PSP（皮层下更为明显的纯腹腔病 区域）由定量途径度量（包括总数和 核和NREM睡眠调节中涉及的核神经元种群和HP-TAU负担）。 由于我们获得了大型AD和PSP患者的纵向队列以及 类似时期的控制和成功的尸检计划，P-TAU和AβPET成像方面的专业知识，深 在神经退行性疾病中的临床睡眠研究经验，老年对照组的组织收集，病例 涵盖全频谱和其他tauopathies，使整个大脑区域的立体学，经验 在人皮层途径和尖端神经病理学方法和脑网络方法中。 这种因素组合创造了一个独特的机会来利用新颖的人类发现，这些发现将为和 补充机械假设和模型系统中的测试。这很关键，因为动物的睡眠 - 唤醒模式和类似广告样的模型与人类的模型不同，实验模型相当模仿非 - 与TAU相关的广告模式相比，AD tauopathies。我们预计我们的发现将为有关的关键信息提供信息 暂时的睡眠和/或昼夜节律的临时顺序以及蛋白质的积累和扩散 AD中的P-T和Aβ等聚集体。除此之外，这项研究的结果还将针对 在广告中治疗障碍的睡眠。