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: 9811219
• 负责人: CHARLES A HOEFFER
• 金额: $ 380.28万
• 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/9811219
• 关键词: Abeta clearance; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animals; Behavioral Assay; Biological; Biological Assay; Brain; Caring; Cerebrospinal Fluid; Chronic; Circadian Dysregulation; Data; Dementia; Disease; Disease Progression; Electrophysiology (science); Etiology; Excessive Daytime Sleepiness; Exhibits; Family; Fright; Genes; Hippocampus (Brain); Immune system; Immunohistochemistry; Impaired cognition; Impairment; Individual; Innate Immune System; Interdisciplinary Study; Knock-out; Knowledge; Link; Mediator of activation protein; Memory impairment; Molecular; Mus; Onset of illness; Outcome Measure; Pathogenesis; Pathologic; Pathology; Patients; Periodicity; Phenotype; Preparation; Process; Production; Protocols documentation; Role; Sampling; Signal Transduction; Sleep; Sleep Architecture; Sleep Fragmentations; Sleep disturbances; Sleeplessness; Slice; Symptoms; Synapses; Synaptic plasticity; Tauopathies; Testing; Time; Tissue Sample; Tissue-Specific Gene Expression; Transgenes; Transgenic Mice; Transgenic Organisms; abeta deposition; circadian; cognitive performance; cohort; cytokine; eIF-2 Kinase; experimental study; feeding; glial activation; human old age (65+); immune activation; improved; inducible gene expression; morris water maze; mouse model; mutant; neuroinflammation; protein expression; response; skills; synaptic function; transcriptome; transcriptome sequencing

PROJECT SUMMARY 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.

项目概要 阿尔茨海默氏病 (AD) 是一种衰老疾病，是最常见的痴呆症，其患病率超过 100 万人。 500 万 65 岁及以上的美国人预计到 2050 年，将有超过 1400 万美国人遭受苦难。 这种疾病的直接财务影响将超过 1.1 万亿美元，因为这一负担尤其沉重。 它会损害记忆力；随着时间的推移，情况会恶化；并且 AD 中的睡眠障碍非常普遍。 睡眠结构和昼夜节律的变化导致白天过度嗜睡 睡眠或昼夜节律紊乱对夜间失眠的影响却鲜为人知。 睡眠促进 Aβ 从大脑中清除，睡眠中断会增加 Aβ 的摄入。 脑脊液中 Aβ 病理学损害核心时钟基因并加剧神经炎症。 这些数据表明，睡眠和昼夜节律紊乱会引发前馈反应，并有助于或 然而，据我们所知，明确的研究表明，AD 会加剧病理学并加速疾病进展。 尚未确定睡眠中断本身对 AD 病理的影响程度。 我们将使用表达可诱导突变淀粉样前体蛋白（APP）转基因的小鼠来暂时 将睡眠中断和突变 APP 表达与随后的 Aβ 沉积和 AD 样病理学分离。 具体来说，我们将：1）确定转基因小鼠的慢性睡眠中断如何改变睡眠过程 突变 APP 表达诱导的病理学；2) 确定睡眠中断是否会加速 AD 发作； 针对先天免疫激活的关键介质并确定对睡眠中断反应的影响 每个目标的结果测量包括认知评估。 突触可塑性；神经胶质细胞激活； 我们的多学科研究团队已经证明。 专业知识并拥有成功完成拟议项目所需的所有技能。 该项目的完成将对该领域产生持续影响，因为我们将阐明 慢性睡眠中断改变 AD 样疾病进展的潜在机制 病理。