Department of Pharmacology, School of Medicine, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
Neuropsychopharmacology. 2010 Jul;35(8):1664-73. doi: 10.1038/npp.2010.13. Epub 2010 Feb 24.
There is much interest in understanding the mechanisms responsible for interactions among stress, aging, memory and Alzheimer's disease. Glucocorticoid secretion associated with early life stress may contribute to the variability of the aging process and to the development of neuro- and psychopathologies. Maternal separation (MS), a model of early life stress in which rats experience 3 h of daily separation from the dam during the first 3 weeks of life, was used to study the interactions between stress and aging. Young (3 months) MS rats showed an altered hypothalamic-pituitary-adrenal (HPA) axis reactivity, depressive-like behavior in the Porsolt swimming test and cognitive impairments in the Morris water maze and new object recognition test that persisted in aged (18 months) rats. Levels of insulin receptor, phosphorylated insulin receptor and markers of downstream signaling pathways (pAkt, pGSK3 beta, pTau, and pERK1 levels) were significantly decreased in aged rats. There was a significant decrease in pERK2 and in the plasticity marker ARC in MS aged rats compared with single MS or aged rats. It is interesting to note that there was a significant increase in the C99 : C83 ratio, A beta levels, and BACE1 levels the hippocampus of MS aged rats, suggesting that in aged rats subjected to early life stress, there was an increase in the amyloidogenic processing of amyloid precursor protein (APP). These results are integrated in a tentative mechanism through which aging interplay with stress to influence cognition as the basis of Alzheimer disease (AD). The present results may provide the proof-of-concept for the use of glucocorticoid-/insulin-related drugs in the treatment of AD.
人们对于理解压力、衰老、记忆和阿尔茨海默病之间相互作用的机制非常感兴趣。与早期生活压力相关的糖皮质激素分泌可能导致衰老过程的可变性，并导致神经和精神病理学的发展。母体分离（MS），是一种早期生活压力模型，在此模型中，大鼠在生命的前 3 周内每天与母鼠分离 3 小时，用于研究压力和衰老之间的相互作用。年轻（3 个月）MS 大鼠表现出下丘脑-垂体-肾上腺（HPA）轴反应性改变、在 Porsolt 游泳测试中出现抑郁样行为以及在 Morris 水迷宫和新物体识别测试中出现认知障碍，这些在老年（18 个月）大鼠中持续存在。胰岛素受体、磷酸化胰岛素受体以及下游信号通路标志物（pAkt、pGSK3β、pTau 和 pERK1 水平）在老年大鼠中显著降低。与单独 MS 或老年大鼠相比，MS 老年大鼠中的 pERK2 和可塑性标志物 ARC 显著减少。有趣的是，MS 老年大鼠海马中 C99：C83 比值、Aβ水平和 BACE1 水平显著增加，这表明在经历早期生活压力的老年大鼠中，淀粉样前体蛋白（APP）的淀粉样形成加工增加。这些结果整合在一个推测的机制中，该机制通过衰老与压力相互作用来影响认知，作为阿尔茨海默病（AD）的基础。目前的结果可能为使用糖皮质激素/胰岛素相关药物治疗 AD 提供概念验证。
