Stress, Glucocorticoids and Alzheimer Disease

描述（由申请人提供）： 阿尔茨海默病（Alzheimer disease，AD）是一种进行性神经退行性疾病，是老年人痴呆的最常见原因。在AD患者中，疾病进展的速度差异很大，在一定程度上与疾病的分期和合并症有关。众所周知，心理应激通过促进各种哺乳动物物种中糖皮质激素（GC）激素的释放来增加下丘脑-垂体-肾上腺（HPA）轴的活性，并且GC激素水平的长期增加与海马体积和记忆缺陷的减少相关。应激、GC活性增加和海马变性之间的关联对于理解AD的神经生物学可能具有特殊的相关性，因为海马变性也是早期AD的标志。然而，关于应激、GC激素和AD进展之间的关系的研究很少。 该项目的总体目标是调查压力通过增加GC水平加速AD进展速度的一般假设。在初步工作中，我们有两个关键发现支持这一一般假设。首先，在一项对阿尔茨海默型（DAT）极轻度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学指标变化率之间存在相关性。第二，在过度产生人类形式的淀粉样前体蛋白（APP）的Tg 2576小鼠中，慢性隔离应激增加了血清皮质酮水平、背景记忆缺陷的严重程度以及海马和皮质中α-淀粉样蛋白斑块的沉积速率。 我们现在建议进一步研究的一般假设，即压力可以通过增加GC活性加速AD的进展速度。首先，我们建议使用神经解剖学以及临床和神经心理学措施来评估血液和唾液皮质醇水平与DAT受试者疾病进展率之间的相关性。其次，我们建议调查隔离应激增加APP转基因小鼠中β-淀粉样蛋白斑块沉积速率的机制，具体而言，确定GC激素在多大程度上是这种机制的一个要素。

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.