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The Molecular Mechanism of Chronic High-Dose Corticosterone-Induced Aggravation of Cognitive Impairment in APP/PS1 Transgenic Mice
Frontiers in Molecular Neuroscience ( IF 3.5 ) Pub Date : 2020-12-17 , DOI: 10.3389/fnmol.2020.613421
Shen-Qing Zhang , Long-Long Cao , Yun-Yue Liang , Pu Wang

Clinical studies have found that some Alzheimer’s disease (AD) patients suffer from Cushing’s syndrome (CS). CS is caused by the long-term release of excess glucocorticoids (GCs) from the adrenal gland, which in turn, impair brain function and induce dementia. Thus, we investigated the mechanism of the effect of corticosterone (CORT) on the development and progression of AD in a preclinical model. Specifically, the plasma CORT levels of 9-month-old APP/PS1 Tg mice were abnormally increased, suggesting an association between GCs and AD. Long-term administration of CORT accelerated cognitive dysfunction by increasing the production and deposition of β-amyloid (Aβ). The mechanism of action of CORT treatment involved stimulation of the expression of BACE-1 and presenilin (PS) 1 in in vitro and in vivo. This observation was confirmed in mice with adrenalectomy (ADX), which had lower levels of GCs. Moreover, the glucocorticoid receptor (GR) mediated the effects of CORT on the stimulation of the expression of BACE-1 and PS1 via the PKA and CREB pathways in neuroblastoma N2a cells. In addition to these mechanisms, CORT can induce a cognitive decline in APP/PS1 Tg mice by inducing apoptosis and decreasing the differentiation of neurons.



中文翻译:

慢性大剂量皮质酮诱导APP / PS1转基因小鼠认知功能障碍的分子机制

临床研究发现,一些阿尔茨海默氏病(AD)患者患有库欣综合征(CS)。CS是由肾上腺长期释放过量的糖皮质激素(GCs)引起的,继而损害大脑功能并诱发痴呆。因此,我们在临床前模型中研究了皮质酮(CORT)对AD发生和发展的作用机理。具体而言,9个月大的APP / PS1 Tg小鼠的血浆CORT水平异常升高,表明GC与AD之间存在关联。长期服用CORT可增加β-淀粉样蛋白(Aβ)的产生和沉积,从而加速认知功能障碍。CORT治疗的作用机制涉及刺激BACE-1和早老素(PS)1的表达。体外体内。肾上腺切除术(ADX)小鼠的GC含量较低,这一发现得到了证实。此外,糖皮质激素受体(GR)介导CORT对刺激BACE-1和PS1表达的影响通过神经母细胞瘤N2a细胞中的PKA和CREB途径。除了这些机制,CORT还可以通过诱导细胞凋亡和减少神经元的分化来诱导APP / PS1 Tg小鼠的认知能力下降。

更新日期:2021-01-16
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