Sleep Disruption and Alzheimer's Disease Pathology

睡眠中断与阿尔茨海默氏病病理学

• 批准号: 10455975
• 负责人: CHARLES A HOEFFER
• 金额: $ 39.03万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455975
• 关键词: Abeta clearance; Administrative Supplement; Affect; Age; Age of Onset; Aging; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; American; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Behavior; Biological Assay; Brain; Calcineurin; Cerebrospinal Fluid; Chromosome 21; Chronic; Circadian Dysregulation; Cognition; Cognitive; Cognitive deficits; Data; Dementia; Disease; Disease Progression; Dose; Down Syndrome; Early Onset Alzheimer Disease; Etiology; Excessive Daytime Sleepiness; Funding; Gene Dosage; Gene Proteins; Genes; Health; Hippocampus (Brain); Human; Impaired cognition; Impairment; Individual; Interdisciplinary Study; Link; Measures; Mediator of activation protein; Memory impairment; Modeling; Molecular; Mus; Nerve Degeneration; Neurobiology; Onset of illness; Outcome; Outcome Measure; Parents; Pathology; Periodicity; Phenotype; Play; Process; Production; Protein Isoforms; Protein Overexpression; Publishing; Quality of life; Research; Role; Signal Transduction; Sleep; Sleep Apnea Syndromes; Sleep Architecture; Sleep Deprivation; Sleep Disorders; Sleep disturbances; Sleeplessness; Synaptic plasticity; Testing; Time; Tissue-Specific Gene Expression; Transgenes; Transgenic Mice; abeta deposition; age related; awake; calcineurin phosphatase; circadian; cognitive performance; cytokine; genetic manipulation; glial activation; human old age (65+); immune activation; improved; mouse Ts65Dn; mouse model; mutant; neuroinflammation; non rapid eye movement; overexpression; protein expression; response; skills; sleep abnormalities; tau Proteins; tau phosphorylation; theories; transcriptome

ABSTRACT (Parent R01 Abstract) Alzheimer’s disease (AD) is a disease of aging. AD is the most common form of dementia, afflicting more than 5 million Americans aged 65 and older. By 2050 it is estimated that more than 14 million Americans will suffer this disease, and that its direct financial impact will exceed $1.1 trillion. AD is particularly burdensome because it impairs memory; it worsens with time; and there is no cure. Sleep disruption in AD is highly prevalent, and changes in sleep architecture and circadian rhythmicity that result in excessive daytime sleepiness and nighttime insomnia are well documented. Less well known is the impact of sleep or circadian disruption on the etiology of the disease. Sleep facilitates Aβ clearance from brain, and sleep disruption increases Aβ in cerebrospinal fluid. Aβ pathology impairs core clock genes and exacerbates neuroinflammation. Collectively, these data suggest that sleep and circadian disruption induce responses that feed forward and contribute to or exacerbate AD pathology and accelerate disease progression. However, to our knowledge definitive studies to determine the extent to which sleep disruption per se contributes to AD pathology have not been conducted. We will use mice expressing an inducible mutant amyloid precursor protein (APP) transgene to temporally dissociate sleep disruption and mutant APP expression from subsequent Aβ deposition and AD-like pathology. Specifically, we will: 1) determine how chronic sleep disruption of transgenic mice alters the course of pathology induced by expression of mutant APP; 2) determine if sleep disruption accelerates AD onset; and 3) target a key mediator of innate immune activation and determine effects on responses to sleep disruption and/or mutant APP expression. Outcome measures for each aim include assessments of cognitive performance; synaptic plasticity; differential gene expression; glial activation; cytokine production; neuroinflammatory signaling; and proteinopathy. Our multidisciplinary research team has demonstrated expertise and possesses all requisite skills to successfully complete the proposed project. Successful completion of this project will have a sustained impact on the field because we will elucidate the extent to which, and potential mechanisms by which, chronic sleep disruption alters the progression of AD-like pathology. (Administrative Supplement) The INCLUDE project focuses on critical health and quality-of-life needs for individuals with Down syndrome. Links between AD and DS are well-documented, but mechanisms underlying them are little understood. NIA is prioritizing research that aims “to understand the molecular mechanism(s) underlying the interplay between aging and neurodegeneration in DS”. A strong candidate for the DS-AD link is the triplication of the Amyloid Precursor Protein (APP) and Regulator of calcineurin1 (RCAN1) genes in trisomy 21. The cleavage product of APP, Aβ, is a defining histopathological marker of AD and promotes sleep dysfunction, whereas RCAN1 affects circadian function and promotes AD-related pathology. This administrative supplement focuses on sleep disruption, APP and RCAN1 as mechanistic DS-AD links. Our preliminary data demonstrate that genetic manipulation to restore Rcan1 to normal levels ameliorates sleep disturbances in a DS model. The research proposed in this supplement is significant because the role of APP overexpression in promoting DS-related sleep or cognitive abnormalities has not been investigated.

抽象的 （母版 R01 摘要）阿尔茨海默病 (AD) 是一种衰老疾病，是 AD 的最常见形式。 预计到 2050 年，将有超过 500 万 65 岁及以上的美国人患有痴呆症。 1400万美国人将遭受这种疾病，其直接经济影响将超过公元1.1万亿美元。 特别麻烦，因为它会损害记忆力；随着时间的推移，情况会恶化，并且无法治愈。 AD 中的紊乱非常普遍，睡眠结构和昼夜节律的变化会导致 白天过度嗜睡和夜间失眠的影响却鲜为人知。 睡眠或昼夜节律紊乱对疾病病因的影响 睡眠促进 Aβ 从大脑中清除，以及 睡眠中断会增加脑脊液中的 Aβ，Aβ 病理会损害核心时钟基因并使其恶化。 总的来说，这些数据表明睡眠和昼夜节律紊乱会引起以下反应： 然而，前馈并促进或恶化 AD 病理并加速疾病进展。 我们的知识权威研究旨在确定睡眠中断本身对 AD 的影响程度 我们将使用表达诱导突变淀粉样蛋白前体的小鼠。 蛋白质（APP）转基因暂时分离睡眠中断和突变APP表达 随后的 Aβ 沉积和 AD 样病理学具体来说，我们将： 1) 确定慢性睡眠的情况。 转基因小鼠的破坏改变了突变 APP 表达诱导的病理过程 2) 确定睡眠中断是否会加速 AD 发病；3) 针对先天免疫激活的关键介质 并确定对睡眠中断和/或突变 APP 表达的反应的影响。 每个目标包括认知表现的评估；差异基因表达； 我们的多学科研究。 团队已展示专业知识并拥有成功完成拟议项目所需的所有技能 该项目的成功完成将对该领域产生持续的影响，因为我们将 阐明慢性睡眠中断改变睡眠的程度和潜在机制 AD 样病理学的进展。 （行政补充）INCLUDE 项目重点关注以下人群的关键健康和生活质量需求： AD 和 DS 之间的联系已被充分记录，但其背后的机制却很明确。 NIA 正在优先开展旨在“了解分子机制”的研究。 DS 中衰老和神经退行性疾病之间相互作用的基础”。DS-AD 联系的一个有力候选者是 三体性中淀粉样前体蛋白 (APP) 和钙调神经磷酸酶 1 (RCAN1) 基因的三倍体 21. APP 的裂解产物 Aβ 是 AD 的组织病理学标志物，可促进睡眠 功能障碍，而 RCAN1 影响昼夜节律功能并促进 AD 相关病理。 行政补充重点关注睡眠干扰、APP 和 RCAN1 作为我们的 DS-AD 机制链接。 初步数据表明，通过基因操作将 Rcan1 恢复至正常水平可改善睡眠 由于 APP 的作用，本补充材料中提出的研究具有重要意义。 过度表达对促进 DS 相关睡眠或认知异常的影响尚未得到研究。

项目成果

Multielectrode array characterization of human induced pluripotent stem cell derived neurons in co-culture with primary human astrocytes.

与原代人星形胶质细胞共培养的人诱导多能干细胞衍生神经元的多电极阵列表征。

• 发表时间: 2024-03-08
• 作者: Lemieux, Maddie R;Freigassner, Bernhard;Thathey, Zahra;Opp, Mark R;Hoeffer, Charles A;Link, Christopher D
• 通讯作者: Link, Christopher D