Cordner Z A, Tamashiro K L K
Cellular and Molecular Medicine Graduate Program, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Transl Psychiatry. 2016 Jul 12;6(7):e854. doi: 10.1038/tp.2016.127.
Stressful life events, activation of the hypothalamic-pituitary-adrenal (HPA) axis and glucocorticoids are now thought to have a role in the development of several neurodegenerative and psychiatric disorders including Alzheimer's disease (AD) through mechanisms that may include exacerbation of cognitive impairment, neuronal loss, and beta-amyloid (Aβ) and tau neuropathology. In the current study, we use a wild-type mouse model to demonstrate that chronic variable stress impairs cognitive function and that aged mice are particularly susceptible. We also find that stress exposure is associated with a 1.5- to 2-fold increase in the expression of Bace1 in the hippocampus of young adult mice and the hippocampus, prefrontal cortex and amygdala of aged mice. Further, the increased expression of Bace1 was associated with decreased methylation of several CpGs in the Bace1 promoter region. In a second series of experiments, exposure to environmental enrichment (EE) prevented the stress-related changes in cognition, gene expression and DNA methylation. Together, these findings re-affirm the adverse effects of stress on cognition and further suggest that aged individuals are especially susceptible. In addition, demonstrating that chronic stress results in decreased DNA methylation and increased expression of Bace1 in the brain may provide a novel link between stress, Aβ pathology and AD. Finally, understanding the mechanisms by which EE prevented the effects of stress on cognition and Bace1 expression will be an important area of future study that may provide insights into novel approaches to the treatment of AD.
现在认为，应激性生活事件、下丘脑-垂体-肾上腺（HPA）轴的激活以及糖皮质激素在包括阿尔茨海默病（AD）在内的几种神经退行性疾病和精神疾病的发生发展中起作用，其机制可能包括加重认知障碍、神经元丢失以及β-淀粉样蛋白（Aβ）和tau神经病理学改变。在本研究中，我们使用野生型小鼠模型来证明慢性可变应激会损害认知功能，并且老年小鼠尤其易感。我们还发现，应激暴露与年轻成年小鼠海马体以及老年小鼠海马体、前额叶皮质和杏仁核中Bace1表达增加1.5至2倍有关。此外，Bace1表达的增加与Bace1启动子区域中几个CpG的甲基化减少有关。在第二系列实验中，暴露于环境富集（EE）可预防与应激相关的认知、基因表达和DNA甲基化变化。总之，这些发现再次证实了应激对认知的不利影响，并进一步表明老年人尤其易感。此外，证明慢性应激导致大脑中DNA甲基化减少和Bace1表达增加，可能会在应激、Aβ病理学和AD之间提供一种新的联系。最后，了解EE预防应激对认知和Bace1表达影响的机制将是未来研究的一个重要领域，可能会为AD的新治疗方法提供见解。
