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Inhibition of STAT3 phosphorylation attenuates impairments in learning and memory in 5XFAD mice, an animal model of Alzheimer's disease.
Journal of Pharmacological Sciences ( IF 3.5 ) Pub Date : 2020-05-22 , DOI: 10.1016/j.jphs.2020.05.009
Moonseok Choi 1 , Hyunju Kim 1 , Eun-Jeong Yang 1 , Hye-Sun Kim 2
Affiliation  

The pathophysiological roles of astrocytes in the reactive state are thought to have important significance in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). However, the detailed mechanisms underlying the transition of astrocytes from the resting state to the reactive state during neurodegenerative disease largely remain to be defined. Here, we investigated the pathways involved in activating astrocytes from the resting state to the reactive state in primary cultured astrocytes treated with oligomeric Aβ and in the hippocampus of 5XFAD mice. Treatment with oligomeric Aβ induced an increase in reactive astrocytes, as assessed by the protein level of glial fibrillary acidic protein (GFAP) and this increase was caused by STAT3 phosphorylation in primary cultured astrocytes. The administration of Stattic, an inhibitor of STAT3, rescued the activation of astrocytes in primary cultured astrocytes and in the hippocampus of 6-month-old 5XFAD mice as well as impairments in learning and memory. Collectively, these results demonstrated that reactive astrocytes in the AD brain are induced via STAT3 and the impairments in learning and memory observed in 5XFAD mice are rescued by STAT3 inhibition, suggesting that the inhibition of STAT3 phosphorylation in astrocytes may be a novel therapeutic target for cognitive impairment in AD.



中文翻译:

抑制STAT3磷酸化可减轻5XFAD小鼠(阿尔茨海默氏病动物模型)的学习和记忆障碍。

星形胶质细胞处于反应状态的病理生理作用被认为在包括阿兹海默氏病(AD)在内的神经退行性疾病的发病机理中具有重要意义。然而,在神经退行性疾病期间星形胶质细胞从静止状态转变为反应状态的详细机制尚待确定。在这里,我们研究了在低聚Aβ处理的原代培养星形胶质细胞和5XFAD小鼠海马中激活星形胶质细胞从静止状态到反应状态的途径。用神经胶质原纤维酸性蛋白(GFAP)的蛋白质水平评估,用低聚Aβ处理可诱导反应性星形胶质细胞增加,而这种增加是由原代培养的星形胶质细胞中STAT3磷酸化引起的。静态管理 STAT3抑制剂STAT3可以挽救6个月大的5XFAD小鼠原代培养的星形胶质细胞和海马中星形胶质细胞的活化以及学习和记忆障碍。总的来说,这些结果表明通过STAT3诱导了AD脑中的反应性星形胶质细胞,并且通过STAT3抑制作用挽救了在5XFAD小鼠中观察到的学习和记忆障碍,这表明星形胶质细胞中STAT3磷酸化的抑制可能是认知的新型治疗靶点。 AD的损害。

更新日期:2020-06-18
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