Sleep Disruption and Alzheimer's Disease Pathology

睡眠中断与阿尔茨海默氏病病理学

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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（父级R01摘要）阿尔茨海默氏病（AD）是一种衰老疾病。广告是最常见的形式痴呆症，折磨了超过500万65岁及以上的美国人。到2050年，据估计 1400万美国人将遭受这种疾病，其直接财务影响将超过1.1万亿美元。广告是特别是伯恩斯，因为它会损害记忆力；随着时间的流逝而恶化；而且无法治愈。睡觉 AD的破坏非常普遍，睡眠结构和昼夜节律的变化导致白天嗜睡过多和夜间失眠。鲜为人知的是对疾病病因的睡眠或昼夜节律破坏。睡眠促进了大脑的Aβ清除率，并且睡眠破坏会增加脑脊液中的Aβ。 Aβ病理会损害核心时钟基因和恶化神经炎症。总的来说，这些数据表明睡眠和昼夜节律影响的反应向前进食并导致或加剧AD病理学并加速疾病进展。但是，要我们的知识确定研究以确定睡眠中断在多大程度上有助于广告尚未进行病理。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）转化为暂时解离睡眠中断和突变APP表达随后的Aβ沉积和类似AD的病理学。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突变应用表达引起的病理学进程。 2）确定睡眠中断是否加速AD发作； 3）针对先天免疫激活的关键介体并确定对对睡眠破坏和/或突变APP表达的反应的影响。结果指标每个目标都包括评估认知表现；突触可塑性；差异基因表达；神经胶质激活;细胞因子产生；神经炎症信号传导；和蛋白质病。我们的多学科研究团队展示了专业知识，并拥有所有必要的技能，可以成功完成建议项目。成功完成该项目将对该领域产生持续的影响，因为我们将阐明慢性睡眠破坏改变的程度以及潜在的机制广告样病理的进展。（行政补充）包括项目的重点是关键的健康和生活质量需求患有唐氏综合症的人。 AD和DS之间的链接有据可查，但是机制是基础的他们几乎没有理解。 NIA正在优先考虑“了解分子机制的研究 DS中的衰老与神经变性之间的相互作用的基础。淀粉样蛋白前体蛋白（APP）和钙调神经磷酸酶（RCAN1）基因的三级三式化在三体中 21。App Ap的裂解产物Aβ是AD的定义组织病理学标记，并促进睡眠功能障碍，而RCAN1影响昼夜节律功能并促进与广告相关的病理。这行政补充侧重于睡眠中断，APP和RCAN1作为机械DS-AD链接。我们的初步数据表明，将RCAN1恢复到正常水平的遗传操作可以改善睡眠 DS模型中的干扰。此补充中提出的研究很重要，因为应用程序的作用尚未研究促进与DS相关的睡眠或认知异常的过表达。