Sleep Disruption and Alzheimer's Disease Pathology

项目摘要 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， 500万65岁及以上的美国人。据估计，到2050年， 它的直接经济影响将超过1.1万亿美元。AD是一种特别沉重的负担，因为 它会损害记忆;它会随着时间的推移而消失;而且没有治愈的方法。AD患者的睡眠中断非常普遍， 睡眠结构和昼夜节律的变化，导致白天过度嗜睡， 夜间失眠是有据可查的不太为人所知的是睡眠或昼夜节律紊乱对睡眠的影响。 疾病的病因。睡眠促进Aβ从大脑中清除，睡眠中断增加Aβ， 脑脊液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诱导的反应是前馈的， 加重AD病理并加速疾病进展。然而，据我们所知， 确定睡眠中断本身对AD病理学的贡献程度尚未进行。 我们将使用表达可诱导的突变淀粉样前体蛋白（APP）转基因的小鼠， 将睡眠中断和突变型APP表达与随后的Aβ沉积和AD样病理分离开来。 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转基因小鼠的睡眠过程。 由突变APP表达诱导的病理学; 2）确定睡眠中断是否加速AD发作;和3） 靶向先天免疫激活的关键介质，并确定对睡眠中断反应的影响 和/或突变APP表达。每个目标的结果测量包括认知评估， 行为;突触可塑性;差异基因表达;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。成功 该项目的完成将对该领域产生持续的影响，因为我们将阐明 以及慢性睡眠中断改变AD样疾病进展的潜在机制。 病理

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.