Sleep Disruption and Alzheimer's Disease Pathology

摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种衰老性疾病。AD是最常见的 痴呆症，困扰着超过500万65岁及以上的美国人。据估计，到2050年， 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。AD是 特别是负担，因为它损害记忆;它与时间有关;并且没有治愈方法。睡眠 AD的中断是非常普遍的，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是有据可查的。鲜为人知的是， 睡眠或昼夜节律紊乱对疾病的病因。睡眠有助于Aβ从大脑中清除， 睡眠中断增加脑脊液中Aβ。Aβ病理损害核心时钟基因并加剧 神经炎症总的来说，这些数据表明，睡眠和昼夜节律紊乱会引起反应， 前馈并促成或加剧AD病理学和加速疾病进展。但要 我们的知识决定性的研究，以确定在何种程度上睡眠中断本身有助于AD 病理学尚未进行。我们将使用表达一种可诱导的突变淀粉样蛋白前体的小鼠， 在一个实施方案中，本发明提供了一种用于暂时分离睡眠中断和突变型APP表达的APP转基因， 随后Aβ沉积和AD样病理。具体来说，我们将：1）确定慢性睡眠 转基因小鼠的破坏改变了由突变APP表达诱导的病理过程; 2） 确定睡眠中断是否加速AD发作;以及3）靶向先天免疫激活的关键介导物 并确定对睡眠中断和/或突变APP表达的反应的影响。结局指标 每个目标都包括评估认知能力;突触可塑性;差异基因表达;神经胶质细胞; 活化;细胞因子产生;神经炎性信号传导;和蛋白质病。我们的多学科研究 团队已展示了专业知识，并拥有成功完成拟议 项目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 阐明在何种程度上，和潜在的机制，其中，慢性睡眠中断改变 AD样病理学进展。 （行政补充）INCLUDE项目的重点是关键的健康和生活质量的需要， 唐氏综合症患者AD和DS之间的联系已得到充分证明，但其背后的机制 他们很少被理解。NIA正在优先考虑旨在“了解分子机制”的研究。 在DS中衰老和神经退行性变之间的相互作用”。DS-AD链路的一个强有力的候选者是 淀粉样前体蛋白（APP）和钙调神经磷酸酶1（RCAN 1）基因在三体中的三重化 21. APP的裂解产物Aβ是AD的组织病理学标志物，可促进睡眠 RCAN 1影响昼夜节律功能并促进AD相关病理。这 管理补充关注睡眠中断、APP和RCAN 1作为机械DS-AD链接。我们 初步数据表明，通过基因操作将Rcan 1恢复到正常水平可以改善睡眠 DS模型中的干扰。本补充中提出的研究具有重要意义，因为APP的作用 在促进DS相关的睡眠或认知异常中的过表达尚未被研究。

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.