Sleep Disruption and Alzheimer's Disease Pathology

摘要 阿尔茨海默病(AD)是一种老年性疾病。广告是最常见的形式 痴呆症，困扰着500多万65岁及以上的美国人。据估计，到2050年，将有超过 1400万美国人将遭受这种疾病，其直接经济影响将超过1.1万亿美元。广告是 负担特别重，因为它会损害记忆；它会随着时间的推移而恶化；而且没有治愈的方法。沉睡 阿尔茨海默病的干扰非常普遍，睡眠结构和昼夜节律的变化导致 白天过度嗜睡和夜间失眠都有很好的记录。不太为人所知的是， 睡眠或昼夜节律紊乱对疾病病因的影响。睡眠有助于β从大脑中清除，而且 睡眠障碍会增加脑脊液中的A-β。一种β病理损害核心时钟基因并加剧 神经炎。总而言之，这些数据表明，睡眠和昼夜节律的紊乱会引发 前馈，促进或加重AD病理，加速疾病进展。然而，为了 我们的知识权威研究，以确定睡眠中断本身对AD的影响程度 尚未进行病理学检查。我们将使用表达可诱导突变的淀粉样前体的小鼠 转基因蛋白质(APP)暂时分离睡眠障碍和突变型APP表达 随后的Aβ沉积和AD样病理。具体地说，我们将：1)确定长期睡眠 干扰转基因小鼠改变突变APP表达诱导的病理过程；2) 确定睡眠中断是否会加速AD的发病；以及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。成果衡量标准 每个目标包括评估认知能力；突触可塑性；差异基因表达；神经胶质细胞 激活；细胞因子的产生；神经炎性信号；和蛋白质病。我们的多学科研究 团队已展示专业知识，并拥有成功完成计划的所有必要技能 项目。这个项目的成功完成将对实地产生持续的影响，因为我们将 阐明慢性睡眠中断改变睡眠质量的程度和可能的机制。 阿尔茨海默病的病理进展。 (行政补编)纳入项目侧重于#年的关键健康和生活质量需求 唐氏综合征患者。AD和DS之间的联系有很好的文档记录，但潜在的机制 人们对它们知之甚少。NIA正在优先进行旨在“了解分子机制”的研究(S) 在DS中衰老和神经退行性变之间的相互作用。DS-AD链路的有力候选者是 三体中淀粉样前体蛋白(APP)和钙调蛋白1(RCAN1)基因的三倍体 21.APP的切割产物Aβ是阿尔茨海默病的组织病理学标志物，促进睡眠 而RCAN1影响昼夜节律功能并促进AD相关的病理。这 行政补充侧重于睡眠中断、APP和RCAN1作为DS-AD的机械性链接。我们的 初步数据表明，通过基因操作将RCAN1恢复到正常水平可以改善睡眠 DS模型中的扰动。本附录中提出的研究具有重要意义，因为APP的作用 促进DS相关睡眠或认知异常的过度表达尚未被调查。

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.