Stress, Glucocorticoids and Alzheimer Disease

压力、糖皮质激素和阿尔茨海默病

• 批准号: 7277679
• 负责人: JOHN G CSERNANSKY
• 金额: $ 33.67万
• 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 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7277679
• 关键词: AP40; Adrenalectomy; Age-Months; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Animals; Appendix; Behavioral; Blood; Boxing; Brain Mapping; Cerebrovascular Disorders; Chronic; Clinical; Clinical dementia rating scale; Cognitive; Condition; Corticosterone; Data Analyses; Dementia; Deposition; Disease; Disease Progression; Disease regression; Dose; Elderly; Elements; Enzyme-Linked Immunosorbent Assay; Glucocorticoids; Half-Life; Hippocampus (Brain); Hormones; Housing; Human; Hydrocortisone; Image; Intercellular Fluid; Investigation; Magnetic Resonance; Magnetic Resonance Imaging; Mammals; Measures; Mediating; Medical; Memory; Memory impairment; Microdialysis; Modeling; Mus; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neurotic Disorders; Numbers; Outcome; Patients; Performance; Personal Satisfaction; Personality inventories; Physiological; Plasma; Procedures; Process; Protons; Psychological Stress; Psychosocial Stress; Randomized; Rate; Reporting; Resolution; Salivary; Sampling; Scanning; Score; Senile Plaques; Serum; Severities; Shapes; Staging; Stress; Structure; Study Subject; Sum; Testing; Tg2576; Time; Tissues; Transgenic Mice; Transgenic Organisms; Treatment/Psychosocial Effects; Weaning; Weight; Work; brain volume; comparison group; day; density; drinking water; hypothalamic-pituitary-adrenal axis; inhibitor/antagonist; mouse model; neuropsychological; psychosocial; research study; secretase; 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（由申请人提供）：阿尔茨海默病（AD）是一种进行性神经退行性疾病，也是老年人痴呆的最常见原因。在 AD 患者中，疾病进展速度差异很大，在一定程度上与疾病阶段和合并症相关。众所周知，心理压力会通过促进多种哺乳动物释放糖皮质激素 (GC) 来增加下丘脑 - 垂体 - 肾上腺 (HPA) 轴的活动，并且长期增加的 GC 激素水平与海马体功能下降有关。容量和记忆力缺陷。压力、GC 活性增加和海马变性之间的关联可能对于理解 AD 的神经生物学具有特殊的相关性，因为海马变性也是早期 AD 的标志。然而，关于压力、GC激素与AD进展之间关系的研究很少。 该项目的总体目标是调查这样一个普遍假设：压力通过增加 GC 水平来加速 AD 的进展速度。在初步工作中，我们做出了两个支持这一一般假设的关键发现。首先，在一项针对极轻度至轻度阿尔茨海默型痴呆 (DAT) 患者的研究中，我们发现 SAM 血清皮质醇浓度与痴呆临床和神经心理学指标的变化率之间存在相关性。其次，在过量产生人类形式淀粉样前体蛋白（APP）的 Tg2576 小鼠中，慢性隔离应激会增加血清皮质酮水平、背景记忆缺陷的严重程度以及海马和皮质中 α-淀粉样斑块的沉积率。 。 我们现在建议进一步研究压力可以通过增加 GC 活性来加速 AD 进展的一般假设。首先，我们建议评估 DAT 受试者血液和唾液皮质醇水平与使用神经解剖学以及临床和神经心理学测量方法测量的疾病进展率之间的相关性。其次，我们建议研究隔离应激增加 APP 转基因小鼠中 β-淀粉样蛋白斑沉积率的机制，具体来说，确定 GC 激素在该机制中的作用程度。