作为阿尔茨海默病潜在治疗靶点的 FoxG1:通过AMPK/mTOR自噬途径调节NLRP3炎症体

IF 3.6 4区 医学 Q3 CELL BIOLOGY
Qi Yun, Si-Fei Ma, Wei-Ning Zhang, Meng Gu, Jia Wang
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引用次数: 0

摘要

越来越多的研究表明,促进小胶质细胞自噬可以阻止阿尔茨海默病(AD)中通过激活 NLRP3 炎性体引发的神经炎症。FoxG1是一种通过调节线粒体功能参与细胞存活的重要转录因子,但它在阿尔茨海默病进程和神经炎症发生过程中的功能仍然未知。在本研究中,我们首先发现Aβ肽诱导AD样神经炎症上调,并下调自噬水平。低剂量Aβ25-35刺激后,FoxG1表达和自噬水平逐渐升高。然而,随着高浓度 Aβ25-35 处理的增加,FoxG1 的表达和自噬水平逐渐下降。此外,FoxG1 对神经系统的细胞活力和自噬也有积极影响。在刺激 Aβ25-35 的同时,我们使用 siRNA 来降低 N2A 细胞中 FoxG1 的表达。我们观察到自噬水平(Beclin1、LC3II、SQSTM1/P62)大幅降低,炎症反应(NLRP3、TNF-α和IL-6)显著增加。此外,我们还发现 FoxG1 的过表达会影响 AMPK/mTOR 自噬通路的激活,而 siRNA-FoxG1 则成功地消除了这一影响。最后,FoxG1抑制了NLRP3炎性体,增强了Aβ25-35诱导的AD样小鼠模型的认知功能。细胞和动物实验证实,FoxG1抑制了NLRP3介导的神经炎症,这与AMPK/mTOR调控的自噬密切相关。综上所述,FoxG1可能是AD病理发展过程中的一个关键节点,并有可能成为治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

FoxG1 as a Potential Therapeutic Target for Alzheimer’s Disease: Modulating NLRP3 Inflammasome via AMPK/mTOR Autophagy Pathway

FoxG1 as a Potential Therapeutic Target for Alzheimer’s Disease: Modulating NLRP3 Inflammasome via AMPK/mTOR Autophagy Pathway

An increasing body of research suggests that promoting microglial autophagy hinders the neuroinflammation initiated though the NLRP3 inflammasome activation in Alzheimer’s disease (AD). The function of FoxG1, a crucial transcription factor involved in cell survival by regulating mitochondrial function, remains unknown during the AD process and neuroinflammation occurs. In the present study, we firstly found that Aβ peptides induced AD-like neuroinflammation upregulation and downregulated the level of autophagy. Following low-dose Aβ25–35 stimulation, FoxG1 expression and autophagy exhibited a gradual increase. Nevertheless, with high-concentration Aβ25–35 treatment, progressive decrease in FoxG1 expression and autophagy levels as the concentration of Aβ25–35 escalated. In addition, FoxG1 has a positive effect on cell viability and autophagy in the nervous system. In parallel with the Aβ25–35 stimulation, we employed siRNA to decrease the expression of FoxG1 in N2A cells. A substantial reduction in autophagy level (Beclin1, LC3II, SQSTM1/P62) and a notable growth in inflammatory response (NLRP3, TNF-α, and IL-6) were observed. In addition, we found FoxG1 overexpression owned the effect on the activation of AMPK/mTOR autophagy pathway and siRNA-FoxG1 successfully abolished this effect. Lastly, FoxG1 suppressed the NLRP3 inflammasome and enhanced the cognitive function in AD-like mouse model induced by Aβ25–35. Confirmed by cellular and animal experiments, FoxG1 suppressed NLRP3-mediated neuroinflammation, which was strongly linked to autophagy regulated by AMPK/mTOR. Taken together, FoxG1 may be a critical node in the pathologic progression of AD and has the potential to serve as therapeutic target.

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来源期刊
CiteScore
7.70
自引率
0.00%
发文量
137
审稿时长
4-8 weeks
期刊介绍: Cellular and Molecular Neurobiology publishes original research concerned with the analysis of neuronal and brain function at the cellular and subcellular levels. The journal offers timely, peer-reviewed articles that describe anatomic, genetic, physiologic, pharmacologic, and biochemical approaches to the study of neuronal function and the analysis of elementary mechanisms. Studies are presented on isolated mammalian tissues and intact animals, with investigations aimed at the molecular mechanisms or neuronal responses at the level of single cells. Cellular and Molecular Neurobiology also presents studies of the effects of neurons on other organ systems, such as analysis of the electrical or biochemical response to neurotransmitters or neurohormones on smooth muscle or gland cells.
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