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.

项目总结