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（由适用提供）：阿尔茨海默氏病（AD）是日益增长的公共卫生危机，没有高效治疗。目前有超过500万美国人患有广告广告，到2050年，这一数字预计将增加到1350万。即使是AD风险的适度降低也将极大地影响公共卫生：将AD的发作推迟5年，预计将使疾病的患病率减半。蛋白质淀粉样蛋白（A€）到大脑中细胞外斑块中的聚集是AD病理学发展的关键步骤，并被认为是在显着细胞和突触损失导致认知障碍和痴呆之前开始的。已经证明，生产的变化增加了25-40％，可以完全保护或引起人类的广告。最近的研究表明，在动物模型和人类的睡眠效果周期中，A水平在清醒期间大脑周围的液体较高，在睡眠过程中较低，即昼夜A级模式，A水平在大脑周围的流体中较高。在发展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浓度和斑块，同时用药物增强睡眠会降低A浓度和斑块。这些发现尚未转化为人类，在我们追求睡眠调制作为AD的预防策略的能力方面留下了巨大的差距。该概念验证的研究提案要直接评估人类是否可以通过睡眠剥夺增加A水平并通过药物增强睡眠来降低。从研究家庭AD招募的45-60岁的健康，认知正常的个人将具有基线家庭睡眠，然后衡量睡眠剥夺，用药物增强睡眠或对照（即遵守基线家庭睡眠时间表）。在睡眠改性过程中，将收集血液和脑脊液，以量化A水平以及使用稳定的同位素标记为氨基酸的动力学（即生产和清除）。拟议的研究不仅会增加我们对AD发病机理的理解，还可能表明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，以确定AD治疗的新目标。