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: 10636812
• 负责人: Lea Tenenholz Grinberg
• 金额: $ 79.36万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10636812
• 关键词: Acceleration; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s neuropathogenesis; Amyloid beta-Protein; Animals; Area; Arousal; Autopsy; Behavior; Biological Models; Brain; Brain Stem; Caregivers; Cell Nucleus; Circadian Dysregulation; Circadian Rhythms; Clinical; Cognitive; Complement; Control Groups; Coupled; Disease Progression; Etiology; Exhibits; Experimental Models; Human; Hypothalamic structure; Image; Impaired cognition; Individual; Institutionalization; Link; Longitudinal cohort; Measures; Methods; Modeling; Napping; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Neurotransmitters; Nuclear; Odds Ratio; Pathology; Patients; Pattern; Phenotype; Polysomnography; Population; Positron-Emission Tomography; Progressive Supranuclear Palsy; Quality of life; Regulation; Role; Sampling; Senile Plaques; Sleep; Sleep Deprivation; Sleep Disorders; Sleep Fragmentations; Sleep Stages; Sleep disturbances; Slow-Wave Sleep; Staging; Symptoms; System; Tauopathies; Testing; Time; abeta deposition; aged; basal forebrain; brain cell; circadian; clinical imaging; cohort; disease natural history; experience; human model; human subject; molecular imaging; neuropathology; non rapid eye movement; novel; programs; protein aggregation; sleep regulation; tau Proteins; tau-1; β-amyloid burden

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.

项目摘要 /摘要 唤醒，睡眠和昼夜节律是阿尔茨海默氏病（AD）的常见发生，通常时间 先前的宽松症状。这种干扰会影响患者和看护人的生活质量，以及 促进制度化。淀粉样蛋白β（Aβ）沉积与睡眠障碍之间的双向相关性 有助于慢波睡眠（SWS）定义和睡眠碎片。我们在 人的睡眠和神经病理学研究表明，患有进行性闭核性麻痹的个体 （PSP）是一种主要的tauopathy，显示出极端的睡眠表型，其睡眠时间短得多。 与tau相关变性为睡眠故障的根本原因的角色，与Aβ无关 沉积。有趣的是，脑干，下丘脑和基本的前脑核与大三式睡眠涉及 调节在皮质区域的缠结之前，通常在 Aβ斑块出现。我们的工作假设是，tau引起的关键脑干变性，下丘脑 和基本的前脑核控制1）SWS； 2）醒来； 3）昼夜节律是睡眠觉醒的基础 AD的行为，在认知能力下降和后来出现的睡眠周期之前出现 干扰和加速Aβ沉积。我们将测试我们的假设对比的睡眠效果行为 通过分析客观睡眠测量的差异，进行性广告阶段与健康对照 临床和分子成像谱以及涉及尾细胞核的定量途径测量， NREM睡眠调节和昼夜节律。此外，我们将添加一个PSP作为阳性对照组。 由于我们的小组专业知识，共同努力的记录以及我们 获得独特特征的临床病理学队列。这种因素组合创造了独特的 利用新颖的人类发现的机会，这些发现将为和补充机械假设和补充 模型系统中的测试。这至关重要，因为动物的睡眠效果图案和类似广告的模型发动机 从人类和实验模型的相当模拟的非AD tauopathies中，而不是与tau相关的AD 模式。我们预计我们的发现将为临时睡眠临时顺序提供关键信息 和/或昼夜节律以及蛋白质聚集体的积累和扩散，例如磷酸-TAU和 Aβ在AD中。除此之外，这项研究的结果还将非正式治疗AD中的睡眠障碍。