Stress, Glucocorticoids and Alzheimer Disease

压力、糖皮质激素和阿尔茨海默病

• 批准号: 7116719
• 负责人: JOHN G CSERNANSKY
• 金额: $ 33.7万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7116719
• 关键词: Alzheimer' s disease; amyloid proteins; behavioral /social science research tag; brain mapping; brain morphology; clinical research; cortisol; enzyme linked immunosorbent assay; genetically modified animals; glucocorticoids; hippocampus; hormone regulation /control mechanism; human old age (65+); human subject; interview; laboratory mouse; longitudinal human study; microdialysis; neuroendocrine system; neuropathology; neuropsychological tests; pathologic process; psychological aspect of aging; psychological stressor; white matter

DESCRIPTION (provided by applicant): Alzheimer disease (AD) is a progressive neurodegenerative disease and the most common cause for dementia in the elderly. Among patients with AD, the rate of disease progression varies considerably, related in some degree to stage of illness and comorbid medical conditions. Psychological stress is well known to increase activity of the hypothalamic-pituitary-adrenal (HP A) axis by promoting release of glucocorticoid (GC) hormones in a variety of mammalian species, and chronically increased levels of GC hormones have been associated with decreases in hippocampal volume and memory deficits. Associations between stress, increased GC activity and hippocampal degeneration may have special relevance for understanding the neurobiology of AD, since hippocampal degeneration is also a marker of early AD. However, there have been few investigations of the relationship between stress, GC hormones and the progression of AD. The overall aim of this project is to investigate the general hypothesis that stress, by increasing GC levels, accelerates the rate of progression of AD. In preliminary work, we have made two key findings that support this general hypothesis. First, in a study of patients with very mild-to-mild dementia of the Alzheimer type (DAT), we found a correlation between SAM serum cortisol concentrations and the rate of change of clinical and neuropsychological measures of dementia. Second, in Tg2576 mice that overproduce the human form of amyloid precursor protein (APP), chronic isolation stress increased serum levels of corticosterone, the severity of deficits in contextual memory, and the rate of deposition of a-amyloid plaques in the hippocampus and cortex. We now propose to further investigate the general hypothesis that stress can accelerate the rate of progression of AD via increases in GC activity. First, we propose to assess correlations between blood and salivary cortisol levels and the rate of disease progression in DAT subjects measured using neuroanatomical as well as clinical and neuropsychological measures. Second, we propose to investigate the mechanism(s) by which isolation stress increases the rate of beta-amyloid plaque deposition in APP-transgenic mice, and in specific, to determine the degree to which GC hormones are an element of this mechanism.

描述(申请人提供)：阿尔茨海默病(AD)是一种进行性神经退行性疾病，是导致老年人痴呆症的最常见原因。在AD患者中，疾病进展的速度差别很大，在某种程度上与疾病的分期和并存的医疗条件有关。众所周知，在多种哺乳动物中，心理应激通过促进糖皮质激素(GC)的释放来增加下丘脑-垂体-肾上腺(HPA)轴的活性，并且长期升高的GC激素水平与海马体积的减少和记忆障碍有关。应激、GC活性升高和海马区退行性变之间的关系对于理解AD的神经生物学可能具有特殊的相关性，因为海马区退行性变也是早期AD的标志。然而，关于应激、GC激素与AD进展之间关系的研究很少。 这个项目的总体目标是调查压力，通过增加GC水平，加速AD进展速度的普遍假设。在初步工作中，我们得出了两个支持这一普遍假设的关键发现。首先，在一项对阿尔茨海默型(DAT)极轻至轻度痴呆患者的研究中，我们发现SAM血清皮质醇浓度与痴呆的临床和神经心理指标的变化率之间存在相关性。其次，在过度产生人类形式的淀粉样前体蛋白(APP)的Tg2576小鼠中，慢性隔离应激增加了血清皮质酮水平，上下文记忆缺陷的严重程度，以及海马区和皮质中a-淀粉样斑块的沉积速度。 我们现在建议进一步研究应激可以通过增加GC活性来加速AD进展的普遍假设。首先，我们建议评估血液和唾液皮质醇水平与DAT受试者疾病进展速度之间的相关性，测量方法包括神经解剖学以及临床和神经心理学测量。其次，我们建议研究隔离应激增加APP转基因小鼠β-淀粉样斑块沉积速率的机制(S)，具体地说，确定GC激素在这一机制中的作用程度。