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 阿尔茨海默氏病的睡眠和昼夜节律：与tau的潜在双向关系 长期以来在有症状的阿尔茨海默氏病（AD）中描述了睡眠和昼夜节律疾病。 我们小组和其他人的最新研究表明，这些灾难是在开始之前可检测到的几年 认知障碍，在AD的临床前阶段。我们的小组表明，调整 小鼠的睡眠对淀粉样斑块沉积有惊人的影响，因为睡眠剥夺增强了斑块伯恩 在增强睡眠的同时减少斑块。此外，我们发现在 间质流体（ISF）暴露的清晰的昼夜节奏，由睡眠/唤醒周期和中央调节 昼夜节律的时钟，以及昼夜节律系统的破坏并促进淀粉样菌斑的形成。尽管 淀粉样菌斑沉积是AD中的第一个已知生物标志物变化，它似乎是淀粉样蛋白的能力 与神经退行性和认知直接相关的斑块以增强tau聚集和扩散 AD的下降。 tau通过大脑传播，Aβ病理对Tau聚集的影响可以是 通过将富含tau的AD脑裂解物注射到Aβ斑块App敲入小鼠的大脑中进行建模。 根据我们的初步数据，我们假设睡眠障碍和昼夜节律破坏可能 通过增加神经元的tau播种物质的释放来促进tau扩散和聚集。我们 提议检查长期限制或增加睡眠对神经元Tau扩散的影响 斑块引起的小鼠tau聚集。因为载脂蛋白E（APOE）强烈影响Aβ和TAU 病理学并与睡眠相互作用，我们将阐明APOE基因型，睡眠之间的相互作用 剥夺，tau扩散和聚集。使用遗传和环境昼夜节律破坏 模型，我们将执行类似的实验，以确定昼夜节律对Tau扩散的影响 和Aβ诱导的tau聚集，并探索昼夜节律的相互作用 Aβ和TAU病理学。最后，我们将研究睡眠障碍之间的纵向关系 人类的昼夜节律碎裂以及临床前Aβ和TAU病理学。我们假设双向 广告病理学与睡眠/昼夜节律之间的关系，其中AD病理干扰 睡眠/昼夜节律功能，而睡眠/昼夜节律促进了AD病理。我们会睡觉或昼夜节 节奏的变化与斑块沉积，tau聚集或认知的未来风险增加有关 人类的下降。这些研究将阐明睡眠，昼夜节律和tau之间的相互作用 小鼠和人类的聚集以及APOE在该过程中的作用。