Sleep and Circadian Rhythms in Alzheimer Disease: Potential bi-directional relationship with tau

阿尔茨海默病中的睡眠和昼夜节律：与 tau 蛋白的潜在双向关系

• 批准号: 9815588
• 负责人: DAVID M. HOLTZMAN
• 金额: $ 369.43万
• 依托单位: WASHINGTON UNIVERSITY
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9815588
• 关键词: ARNTL gene; Acute; Affect; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Apolipoprotein E; Appearance; Behavior; Biological Markers; Brain; Brain Diseases; Chronic; Circadian Dysregulation; Circadian Rhythms; Cognitive; Data; Deposition; Disease; Diurnal Rhythm; Event; Exhibits; Functional disorder; Future; Genetic; Genotype; Hour; Human; Impaired cognition; Individual; Injections; Intercellular Fluid; Knock-in Mouse; Link; Measurement; Mediating; Memory Loss; Modeling; Mus; Nerve Degeneration; Neurons; Participant; Pathogenesis; Pathologic; Pathology; Peptides; Pharmacology; Phase; Polysomnography; Preventive Intervention; Preventive therapy; Process; Proteins; Regulation; Risk; Role; Seeds; Senile Plaques; Sleep; Sleep Deprivation; Sleep Wake Cycle; Sleep disturbances; Synapses; System; Tauopathies; Transcript; Wild Type Mouse; actigraphy; amyloid formation; base; circadian; circadian pacemaker; cohort; common symptom; design; experimental study; hypocretin; in vivo; mouse model; neuroinflammation; new technology; non-genetic; pre-clinical; tau Proteins; tau aggregation

PROJECT SUMMARY Sleep and Circadian Rhythms in Alzhiemer’s Disease: Potential bi-directional relationship with tau Sleep and circadian rhythm disturbances have long been described in symptomatic Alzheimer’s Disease (AD). Recent studies by our group and others show that these disturbances are detectable years before the onset of cognitive impairment, during the preclinical phase of AD. Our group has shown that modulating the amount of sleep in mice has striking effects on amyloid plaque deposition, as sleep deprivation augments plaque burden while sleep enhancement reduces plaques. Moreover, we have found that levels of Aβ peptide in the interstitial fluid (ISF) exhibit clear diurnal rhythms which are regulated by the sleep/wake cycle and the central circadian clock, and that disruption of the circadian system and promotes amyloid plaque formation. While amyloid plaque deposition is the first known biomarker change in AD, it appears to be the ability of amyloid plaques to augment tau aggregation and spreading that is directly linked to neurodegeneration and cognitive decline in AD. Tau spreading though the brain, and the effect of Aβ pathology on tau aggregation, can be modeled by injection of tau-enriched AD brain lysate into the brain of Aβ plaque-bearing APP knock-in mice. Based on our preliminary data, we hypothesize that sleep disturbance and circadian rhythm disruption may promote tau spreading and aggregation by increasing the release of tau seeding species from neurons. We propose to examine the impact of chronically restricting or increasing sleep on neuronal tau spreading and plaque-induced tau aggregation in mice. Because apolipoprotein E (apoE) strongly influence Aβ and tau pathology and interacts with sleep, we will elucidate the interaction between APOE genotype, sleep deprivation, and tau spreading and aggregation. Using both genetic and environmental circadian disruption models, we will perform similar experiments to determine the effects of circadian disruption on tau spreading and Aβ-induced tau aggregation, and explore the interplay between circadian disruption, sleep, and apoE on Aβ and tau pathology. Finally, we will examine the longitudinal relationship between sleep disturbance, circadian fragmentation, and preclinical Aβ and tau pathology in humans. We hypothesize a bidirectional relationship between AD pathology and sleep/circadian rhythms, in which AD pathology disrupts sleep/circadian function, while sleep/circadian disruption promotes AD pathology. We will if sleep or circadian rhythm changes are associated with increased future risk of plaque deposition, tau aggregation, or cognitive decline in humans. These studies will elucidate the interaction between sleep, circadian rhythms, and tau aggregation in mice and humans, as well as the role of apoE in that process.

项目摘要 阿尔茨海默病患者的睡眠和昼夜节律：与tau蛋白的潜在双向关系 睡眠和昼夜节律紊乱长期以来一直被描述在症状性阿尔茨海默病（AD）。 我们小组和其他人最近的研究表明，这些干扰是可检测的发病前几年， 认知障碍，在AD的临床前阶段。我们的团队已经证明， 小鼠睡眠对淀粉样斑块沉积有显著影响，因为睡眠剥夺会增加斑块负担 而睡眠增强可以减少斑块。此外，我们发现，Aβ肽水平在 间质液（ISF）表现出明显的昼夜节律，其由睡眠/觉醒周期和中枢神经系统调节。 昼夜节律钟，以及昼夜节律系统破坏和促进淀粉样蛋白斑形成。而 淀粉样蛋白斑块沉积是AD中第一个已知的生物标志物变化，它似乎是淀粉样蛋白 斑块增加tau蛋白聚集和扩散，直接与神经变性和认知功能障碍有关。 AD下降。Tau在大脑中的扩散以及Aβ病理学对Tau聚集的影响，可以被认为是一个重要的因素。 通过将tau富集的AD脑裂解物注射到携带Aβ斑块的APP敲入小鼠的脑中来建模。 根据我们的初步数据，我们假设睡眠障碍和昼夜节律紊乱可能 通过增加神经元中tau种子种类的释放来促进tau扩散和聚集。我们 建议研究长期限制或增加睡眠对神经元tau蛋白扩散的影响， 噬菌斑诱导的小鼠中的tau聚集。由于载脂蛋白E（apoE）强烈影响Aβ和tau蛋白， 我们将阐明APOE基因型、睡眠和睡眠之间的相互作用， 剥夺和tau蛋白扩散和聚集。利用遗传和环境的昼夜节律干扰 模型，我们将进行类似的实验来确定昼夜节律中断对tau传播的影响 和Aβ诱导的tau蛋白聚集，并探讨昼夜节律破坏，睡眠和apoE之间的相互作用， Aβ和tau病理学。最后，我们将研究睡眠障碍， 昼夜节律片段化和人类临床前Aβ和tau病理学。我们假设一个双向的 AD病理学与睡眠/昼夜节律之间的关系，其中AD病理学破坏 睡眠/昼夜节律功能，而睡眠/昼夜节律破坏促进AD病理。如果睡眠或昼夜节律 节律变化与斑块沉积、tau蛋白聚集或认知功能障碍的未来风险增加相关。 人类的衰落。这些研究将阐明睡眠、昼夜节律和tau蛋白之间的相互作用。 在小鼠和人类中的聚集，以及apoE在这一过程中的作用。