Effects of Acute Stress Exposure on Plasma beta-amyloid Levels

急性应激暴露对血浆 β-淀粉样蛋白水平的影响

• 批准号: 10575514
• 负责人: MARA MATHER
• 金额: $ 21.36万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10575514
• 关键词: Acute; Address; Adrenal Glands; Affect; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Animal Model; Animals; Biological Markers; Blood specimen; Brain; Cerebrospinal Fluid; Correlation Studies; Deposition; Development; Disease; Disease Marker; Disease Outcome; Disease Progression; Encephalitis; Endocrine; Etiology; Exposure to; Feedback; Functional disorder; Future; Glucocorticoids; Hand; Hormones; Hour; Human; Hydrocortisone; Hypothalamic structure; Ice; Impairment; Individual; Laboratories; Life; Link; Literature; Measures; Nerve Degeneration; Observational Study; Participant; Pathogenesis; Pathway interactions; Patients; Persons; Physiological; Pituitary Gland; Pituitary-Adrenal System; Plasma; Play; Post-Traumatic Stress Disorders; Process; Production; Reaction; Recording of previous events; Reporting; Research; Role; Salivary; Series; Stress; Stressful Event; System; Testing; Time; Translating; Veterans; Videotape; Water; Woman; Work; acute stress; aged; allostatic load; biological adaptation to stress; disease phenotype; glucose metabolism; heart rate variability; hyperphosphorylated tau; hypothalamic-pituitary-adrenal axis; insight; interstitial; longitudinal analysis; men; middle age; mild cognitive impairment; neuroinflammation; response; restraint stress; social; stressor; theories

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.

项目摘要 理论上将压力参与了阿尔茨海默氏病（AD）的发病机理和进展 模型，应力激素可以诱导与AD相似的状态，例如葡萄糖代谢受损， 大脑的炎症，并在大脑中炎症-淀粉样蛋白（A）和高磷酸化的tau。 不幸的是，压力对人类AD发病机理的影响更多是难以建立。 人体中的压力与AD之间的关系仅限于相关研究。 轻度认知障碍，并且在整个中具有较高的应激激素（皮质醇）水平，并且不 有效关闭压力响应。 与更快的疾病进展相关。 创伤后条纹疾病具有两倍的发展，而对女性的一系列研究 表明中年的压力与以后生活中的AD诊断风险增加有关 这是对以后的AD的长期和可能的累积累积效应，这些，这些 观察性研究并未足够解决将压力暴露与AD风险联系起来的潜在机制。 特别是，我们缺乏有关压力源是否影响人类的A水平的信息 这一差距问：“急性压力会增加人类的水平吗？” 血浆对急性实验室压力源的呼吸，社会上评估了38个 18-65岁的男女将完成一个负责人，涉及将手握在冰水中 参与者对压力源的反应是录像带。 在两个会话中，都要完成一项非压力的任务，以代替Tressor。 将使用唾液不含皮质醇水平的变化以及心率变异性和血液来测量激活 将收集样品，以测量我们的应力反应。 水平遗嘱的遗嘱增加，心率的可变性将在压力会议期间降低，但在控制期间不会 会议。 对应激的响应将与应激的血浆A的大小有关。 了解压力如何触发与广告相关的过程是理解压力的重要步骤 为人们的广告发展和进步做出贡献。 通过将急性应力对动物模型中观察到的A产生的影响转化为应力AD文献 人类。 压力增加了生命后期的AD风险和发病机理，并推动了AD开发研究的未来途径 和AD治疗方案，尤其是在疾病的前驱阶段，减轻应激时 相关的生产可能可以防止AD致病发生和进展。