Effects of Acute Stress Exposure on Plasma beta-amyloid Levels

项目摘要 应激被认为与阿尔茨海默病（AD）的发病机制和进展有关。在动物 在模型中，应激激素可以诱导类似于AD中所见的状态，如葡萄糖代谢受损， 脑炎症，以及脑中β-淀粉样蛋白（A β）和过度磷酸化tau蛋白的增加。 不幸的是，压力对人类AD发病机制的影响更难以确定。目前 人类应激与AD的关系仅限于相关性研究。例如， 轻度认知障碍和AD患者全天的应激激素（皮质醇）水平较高， 有效地关闭了应激反应。其他研究表明，更大的压力系统功能障碍是 与更快的疾病进展有关。还有其他研究表明，有过 创伤后应激障碍的AD发病率增加了两倍，而一系列针对女性的研究表明， 提示中年的压力与以后生活中AD诊断的风险增加有关。这些研究表明 有一个长期的和可能的累积效应的压力暴露对以后的AD结果，然而，这些 观察性研究没有充分说明将压力暴露与AD风险联系起来的潜在机制。 特别是，我们缺乏关于压力是否会影响人类A β水平的信息。该提案针对 通过问“急性压力是否会增加人类的A β水平？”我们将通过测量 血浆A β对急性实验室应激源的反应，社会评价的冷加压试验。三十八 年龄在18-65岁之间的女性和男性将完成一项实验室压力刺激，包括将他们的手放在冰水中， 当他们对压力源的反应被录像时，参与者不知道的时间量。参与者将 也可以在单独的会议中完成一项非压力性任务来代替压力源。在这两次会议上， 将使用唾液游离皮质醇水平和心率变异性的变化来测量激活，并且血液 将收集样本用于测量对压力的反应。我们预测皮质醇和血浆A β 水平将增加，心率变异性将降低，在应激过程中，但不是在控制期间 上网时段我们进一步预测，唾液游离皮质醇和心率变异性的变化幅度， 对应激的反应将与血浆A β对应激的反应的变化幅度有关。 了解压力如何触发AD相关过程是了解压力如何影响AD的重要一步。 有助于AD的发展和进展。这一建议将解决这一重要差距， 通过将动物模型中观察到的急性应激对A β产生的影响转化为 人类这项研究的发现将有助于开发一种机制途径， 压力增加了以后生活中AD风险和发病机制，并推动了AD发展的未来研究途径 和AD治疗选择，特别是在疾病的前驱期，当减少压力- 相关的A β产生可能防止AD的发病和进展。

PROJECT SUMMARY Stress is theorized to be involved in Alzheimer’s disease (AD) pathogenesis and progression. In animal models, stress hormones can induce states similar to those seen in AD, such as impaired glucose metabolism, inflammation of the brain, and increased -amyloid (A) and hyperphosphorylated tau in the brain. Unfortunately, the effect of stress on AD pathogenesis in humans is more difficult to establish. Currently, the relationship between stress and AD in humans is limited to correlational studies. For instance, individuals with mild cognitive impairment and AD have higher stress hormone (cortisol) levels throughout the day and do not efficiently shut down the stress response. Other work suggests that greater stress system dysfunction is associated with more rapid disease progression. Still other research suggests that veterans with a history of post-traumatic stress disorder had a two-fold increase in AD development, while a series of studies in women suggests that stress in midlife is related to an increased risk of AD diagnosis later in life. These studies suggest there is a long-term and possibly cumulative effect of stress exposure on later AD outcomes, however, these observational studies do not sufficiently address potential mechanisms connecting stress exposure to AD risk. In particular, we lack information about whether stressors influence A levels in humans. This proposal targets this gap by asking, “does acute stress increase A levels in humans?” We will achieve this by measuring the plasma A response to an acute laboratory stressor, the socially evaluated cold pressor test. Thirty-eight women and men aged 18-65 will complete a laboratory stressor involving holding their hand in ice water for an amount of time unknown to the participant while their reactions to the stressor are videotaped. Participants will also complete a non-stressful task in lieu of the stressor in a separate session. At both sessions, stress activation will be measured using changes in salivary free cortisol levels and in heart rate variability, and blood samples will be collected for measuring the A response to stress. We predict that cortisol and plasma A levels will increase, and heart rate variability will decrease, during the stress session but not during the control session. We further predict that the magnitude of change in salivary free cortisol and heart rate variability in response to stress will be related to the magnitude of change of plasma A in response to stress. Understanding how stress may trigger AD-related processes is an important step in understanding how stress contributes to AD development and progression in people. This proposal will address this important gap in the stress-AD literature by translating the effects of acute stress on A production observed in animal models to humans. Findings from this study will help develop a mechanistic pathway for how repeated or cumulative stress increases AD risk and pathogenesis later in life and drive future avenues of research in AD development and AD treatment options, especially during the prodromal stage of the disease when decreasing stress- related A production might protect against AD-pathogenesis and progression.