SLEEP: A POTENTIAL NOVEL MODULATOR OF ALZHEIMER'S DISEASE PATHOLOGY

睡眠：阿尔茨海默病病理学的潜在新型调节剂

• 批准号: 8755446
• 负责人: Brendan Patrick Lucey
• 金额: $ 11.44万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8755446
• 关键词: Adult; Affect; Age; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; American; Amino Acids; Amyloid; Amyloid Proteins; Amyloid beta-Protein Precursor; Amyloid deposition; Animal Model; Award; Basic Science; Behavioral; Blood; Brain; Cells; Cerebrospinal Fluid; Clinical Research; Cognitive; Cohort Studies; Collection; Dementia; Deposition; Development; Disease; Environmental Risk Factor; Foundations; Future; Genetic; Home environment; Hour; Human; Impaired cognition; Individual; Infusion procedures; Intercellular Fluid; Kinetics; Lead; Learning; Left; Liquid substance; Measures; Mentors; Metabolic Clearance Rate; Modification; Monitor; Mus; Neurofibrillary Tangles; Outcome; Pathogenesis; Pathology; Pattern; Pharmaceutical Preparations; Phase; Polysomnography; Prevalence; Prevention strategy; Primary Prevention; Production; Public Health; Recruitment Activity; Research; Resources; Role; Sampling; Schedule; Secondary Prevention; Senile Plaques; Sleep; Sleep Deprivation; Sleep Wake Cycle; Sodium Oxybate; Stable Isotope Labeling; Synapses; Testing; Time; Transgenic Mice; Translating; Wakefulness; aged; apolipoprotein E-4; career; design; diet and exercise; effective therapy; extracellular; familial Alzheimer disease; improved; innovation; novel; patient oriented; pre-clinical; prevent; protein aggregation; public health relevance; research study; response; skills; tau aggregation

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a growing public health crisis that has no highly effective treatment. Over 5 million Americans currently suffer from AD and this number is expected to increase to 13.5 million by 2050. Even a modest reduction in the risk of AD would impact public health tremendously: delaying the onset of AD by 5 years is predicted to halve the prevalence of the disease. The aggregation of the protein amyloid-¿ (A¿) into extracellular plaques in the brain is a key step in the development of AD pathology and is hypothesized to begin before significant cell and synaptic loss lead to cognitive impairment and dementia. Changes in A¿ production by 25-40% have been shown to completely protect or cause AD in humans. Recent research has shown that A¿ levels fluctuate with the sleep-wake cycle in both animal models and humans: A¿ levels are higher in the fluid around the brain during wakefulness and lower during sleep, i.e. a diurnal A¿ pattern. In animal models of transgenic mice that develop amyloid deposition, sleep deprivation increased both A¿ concentrations and plaques in the brain while enhancing sleep with medication reduced both A¿ concentrations and plaques. These findings have not been translated to humans, leaving a critical gap in our ability to pursue sleep modulation as a preventive strategy for AD. This proof-of-concept study proposes to directly assess in humans if A¿ levels can be increased by sleep deprivation and decreased by sleep enhancement with medication. Healthy, cognitively normal individuals aged 45-60 years recruited from a longitudinal cohort studying familial AD will have baseline home sleep measured followed by sleep deprivation, sleep enhancement with a medication, or control (i.e. adhere to baseline home sleep schedule). During sleep modification, blood and cerebrospinal fluid will be collected to quantify A¿ levels as well as kinetics (i.e. production and clearance) using stable isotope labeled amino acids. The proposed study not only will increase our understanding of the pathogenesis of AD, it may suggest innovative AD prevention and treatment approaches that involve sleep therapies and may launch a novel field of research that identifies new targets for AD treatment.

描述（由申请人提供）：阿尔茨海默病（AD）是一种日益严重的公共卫生危机，没有高效的治疗方法。目前有超过500万美国人患有AD，预计到2050年这一数字将增加到1350万。即使是AD风险的适度降低也会对公共卫生产生巨大影响：预计将AD发病时间推迟5年将使该疾病的患病率减半。淀粉样蛋白（A）聚集到脑中的细胞外斑块中是AD病理学发展的关键步骤，并且假设在显著的细胞和突触损失导致认知障碍和痴呆之前开始。A？产生的25-40%的变化已被证明完全保护或导致人类AD。最近的研究表明，在动物模型和人类中，A <$水平随着睡眠-觉醒周期而波动：清醒期间大脑周围液体中的A <$水平较高，睡眠期间较低，即昼夜A <$模式。在发生淀粉样蛋白沉积的转基因小鼠的动物模型中，睡眠剥夺增加了大脑中的A？浓度和斑块，而用药物增强睡眠则减少了A？浓度和斑块。这些发现尚未转化为人类，这使得我们将睡眠调节作为AD预防策略的能力存在重大差距。这项概念验证研究提出直接评估人类的A水平是否可以通过睡眠剥夺来增加，并通过药物增强睡眠来降低。从研究家族性AD的纵向队列中招募的年龄为45-60岁的健康、认知正常的个体将测量基线家庭睡眠，然后进行睡眠剥夺、用药物增强睡眠或对照（即遵守基线家庭睡眠时间表）。在睡眠调整期间，将收集血液和脑脊液，以使用稳定同位素标记的氨基酸定量A？水平以及动力学（即产生和清除）。这项拟议的研究不仅将增加我们对AD发病机制的了解，还可能提出涉及睡眠疗法的创新AD预防和治疗方法，并可能启动一个新的研究领域，为AD治疗确定新的目标。