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

描述(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，目前还没有非常有效的治疗方法。目前有500多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。即使是AD风险的适度降低也会极大地影响公众健康：将AD的发病时间推迟5年，预计将使疾病流行率减半。蛋白质淀粉样蛋白(A？)聚集到脑内细胞外斑块是AD病理发展的关键步骤，假设在显著的细胞和突触丢失导致认知障碍和痴呆之前就开始了。已有证据表明，A？的产生变化25%-40%可以完全保护人类或导致人类患上阿尔茨海默病。最近的研究表明，在动物模型和人类中，A？水平都随着睡眠-觉醒周期而波动：A？水平在清醒时大脑周围的液体中较高，而在睡眠时较低，即白天A？模式。在产生淀粉样蛋白沉积的转基因小鼠的动物模型中，睡眠不足增加了大脑中A？的浓度和斑块，而药物改善睡眠则降低了A？的浓度和斑块。这些发现还没有被翻译到人类身上，这在我们寻求睡眠调节作为AD预防策略的能力上留下了一个关键的缺口。这项概念验证研究建议在人类中直接评估睡眠剥夺是否会增加A？水平，而药物改善睡眠是否会降低A？水平。从研究家族性阿尔茨海默病的纵向队列中招募的年龄在45-60岁之间的健康、认知正常的人将被测量基线家庭睡眠，然后被剥夺睡眠，用药物增强睡眠，或对照(即坚持基线家庭睡眠时间表)。在睡眠改善期间，将收集血液和脑脊液，以使用稳定的同位素标记氨基酸来量化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发病机制的理解，还可能提出创新的AD预防和治疗方法，包括睡眠疗法，并可能启动一个新的研究领域，确定AD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.