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

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，没有非常有效的治疗方法。目前有超过500万美国人患有阿尔茨海默病，预计到2050年这一数字将增加到1350万。即使阿尔茨海默病风险的适度降低也会极大地影响公共卫生：预计将阿尔茨海默病的发病推迟5年将使该疾病的患病率减半。淀粉样蛋白-¿（A¿）在大脑中聚集成细胞外斑块是AD病理发展的关键步骤，并且假设在显著的细胞和突触丧失导致认知障碍和痴呆之前就开始了。已证明，A¿产生25-40%的变化可以完全保护或导致人类AD。最近的研究表明，动物模型和人类的A -¿水平都随着睡眠-觉醒周期而波动：清醒时大脑周围液体中的A -¿水平较高，睡眠时较低，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，而通过药物增强睡眠减少了A -¿浓度和斑块。这些发现还没有转化到人类身上，在我们追求睡眠调节作为AD预防策略的能力上留下了一个关键的空白。这项概念验证研究建议直接评估人类A¿水平是否可以通过睡眠剥夺而增加，并通过药物增强睡眠而降低。从家族性阿尔茨海默病的纵向队列研究中招募了45-60岁的健康、认知正常的个体，测量了基线家庭睡眠，然后进行了睡眠剥夺、药物增强睡眠或控制（即坚持基线家庭睡眠时间表）。在睡眠矫正期间，将收集血液和脑脊液，使用稳定同位素标记的氨基酸来量化A¿水平和动力学（即产生和清除）。这项研究不仅将增加我们对阿尔茨海默病发病机制的了解，还可能提出包括睡眠疗法在内的创新阿尔茨海默病预防和治疗方法，并可能开启一个新的研究领域，确定阿尔茨海默病治疗的新靶点。

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.