Effects of Acute Stress Exposure on Plasma beta-amyloid Levels

项目总结 压力被认为与阿尔茨海默病(AD)的发病和发展有关。在动物身上 模型中，应激激素可以诱导类似于AD的状态，如葡萄糖代谢受损， 脑部炎症，以及大脑中-淀粉样蛋白(A)和过度磷酸化的tau增加。 不幸的是，应激在人类AD发病机制中的作用更难确定。目前， 人类应激与阿尔茨海默病之间的关系仅限于相关研究。例如，具有以下特征的个人 轻度认知障碍和阿尔茨海默病全天的应激激素(皮质醇)水平较高，而不是 有效地关闭压力反应。其他研究表明，更大的压力系统功能障碍 与更快的疾病进展有关。还有其他研究表明，有退伍军人病史的 创伤后应激障碍在AD的发展中增加了两倍，而一系列针对女性的研究 表明中年压力与晚年被诊断为阿尔茨海默病的风险增加有关。这些研究表明 然而，压力暴露对后来的AD结果有长期的、可能是累积的影响，然而， 观察性研究没有充分解决压力暴露与AD风险之间的潜在机制。 特别是，我们缺乏关于应激源是否影响人类A水平的信息。这项提案针对的是 通过问“急性应激是否会增加人类体内的A-水平？”我们将通过测量 血浆A对急性实验室应激源的反应，即社会评估的冷加压试验。三十八岁 年龄在18-65岁的女性和男性将完成一项实验室应激源，包括在冰水中握手一段时间 当参与者对应激源的反应被录像时，参与者不知道的时间。参与者将 另外，在单独的会议中完成一项无压力的任务，以代替压力源。在这两个会议上，都有压力 激活将通过唾液游离皮质醇水平和心率变异性以及血液的变化来衡量 将收集样本以测量A对压力的反应。我们预测皮质醇和血浆A 在应激过程中，水平会增加，心率变异性会降低，但在对照期间不会 会议。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 应激反应与血浆A-应激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 有助于阿尔茨海默病的发展和进展。这项提议将解决这一重要差距， 应激-AD文献将动物模型中观察到的急性应激对产生的影响转化为 人类。这项研究的发现将有助于开发一条机制路径，以确定重复或累积的程度 应激增加了AD的风险和晚年的发病机制，并推动了AD发展的未来研究途径 和AD的治疗选择，特别是在疾病的前驱阶段，当减少压力时- 相关A的产生可能对AD的发病和进展具有保护作用。

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.