在体外和体内阿尔茨海默病模型中,青蒿素通过调节IRE1/NF-κB信号通路减轻星形细胞过度激活和神经炎症

IF 7.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Lei Chen, Xia Zhao, Rui Sheng, Philip Lazarovici, Wenhua Zheng
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引用次数: 0

摘要

最近的研究表明,神经炎症和神经胶质活性升高,特别是星形胶质细胞过度激活,与阿尔茨海默病(AD)有关。淀粉样蛋白(Aβ)的异常积累诱导内质网应激并激活星形胶质细胞。研究发现,一线抗疟疾药物青蒿素(ART)具有神经保护作用。然而,其对星形胶质细胞的影响尚不清楚。本研究以Aβ1-42诱导的星形胶质细胞培养和3× Tg-AD小鼠为体内和体外模型,探讨ART对AD相关星形胶质细胞过度激活的影响及其机制。ART通过抑制IRE1磷酸化和NF-κB通路,以及与内质网应激相关的激活剂和抑制剂的应用,证明了IRE1 WT和IRE1- k599a的过表达(激酶活性失效),减弱了a β1-42诱导的星形胶质细胞激活、内质网应激和星形胶质细胞培养中的炎症反应。此外,ART可减轻星形胶质细胞对共培养神经元的不良影响,恢复其神经营养功能,防止Aβ1-42处理过程中神经元的凋亡。在3×Tg-AD小鼠中,ART治疗改善了认知功能,减少了星形胶质细胞过度激活、神经炎症、内质网应激和神经元凋亡。此外,ART可减弱AD小鼠IRE1/NF-κB通路活性的上调。通过腺相关病毒在AD小鼠体内的星形胶质细胞特异性过表达IRE1逆转了ART的改善作用。我们的研究结果表明,ART通过调节IRE1/NF-κB信号通路,在体外和体内AD模型中抑制星形细胞过度激活和神经炎症,从而增强神经元功能。这项研究强调了ART治疗AD的潜力,并强调了调节内质网应激-炎症周期和使星形细胞-神经元通讯正常化的重要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Artemisinin alleviates astrocyte overactivation and neuroinflammation by modulating the IRE1/NF-κB signaling pathway in in vitro and in vivo Alzheimer's disease models.

Recent studies have shown that neuroinflammation and heightened glial activity, particularly astrocyte overactivation, are associated with Alzheimer's disease (AD). Abnormal accumulation of amyloid-beta (Aβ) induces endoplasmic reticulum (ER) stress and activates astrocytes. Artemisinin (ART), a frontline anti-malarial drug, has been found to have neuroprotective properties. However, its impact on astrocytes remains unclear. In this study, we used Aβ1-42 induced astrocyte cultures and 3 × Tg-AD mice as in vitro and in vivo models, respectively, to investigate the effects of ART on AD related astrocyte overactivation and its underlying mechanisms. ART attenuated Aβ1-42-induced astrocyte activation, ER stress, and inflammatory responses in astrocyte cultures by inhibiting IRE1 phosphorylation and the NF-κB pathway, as evidenced by the overexpression of IRE1 WT and IRE1-K599A (kinase activity invalidated), along with application of activators and inhibitors related to ER stress. Furthermore, ART alleviated the detrimental effects and restored neurotrophic function of astrocytes on co-cultured neurons, preventing neuronal apoptosis during Aβ1-42 treatment. In 3 × Tg-AD mice, ART treatment improved cognitive function and reduced astrocyte overactivation, neuroinflammation, ER stress, and neuronal apoptosis. Moreover, ART attenuated the upregulation of IRE1/NF-κB pathway activity in AD mice. Astrocyte-specific overexpression of IRE1 via adeno-associated virus in AD mice reversed the ameliorating effects of ART. Our findings suggest that ART inhibits astrocyte overactivation and neuroinflammation in both in vitro and in vivo AD models by modulating the IRE1/NF-κB signaling pathway, thereby enhancing neuronal functions. This study underscores the therapeutic potential of ART in AD and highlights the significance of modulating the ER stress-inflammatory cycle and normalizing astrocyte-neuron communication.

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来源期刊
Free Radical Biology and Medicine
Free Radical Biology and Medicine 医学-内分泌学与代谢
CiteScore
14.00
自引率
4.10%
发文量
850
审稿时长
22 days
期刊介绍: Free Radical Biology and Medicine is a leading journal in the field of redox biology, which is the study of the role of reactive oxygen species (ROS) and other oxidizing agents in biological systems. The journal serves as a premier forum for publishing innovative and groundbreaking research that explores the redox biology of health and disease, covering a wide range of topics and disciplines. Free Radical Biology and Medicine also commissions Special Issues that highlight recent advances in both basic and clinical research, with a particular emphasis on the mechanisms underlying altered metabolism and redox signaling. These Special Issues aim to provide a focused platform for the latest research in the field, fostering collaboration and knowledge exchange among researchers and clinicians.
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