METTL3/IGF2BP2/ i - κ b α轴通过调节小胶质细胞M1/M2极化参与阿尔茨海默病的神经炎症。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international Pub Date : 2025-03-17 DOI:10.1016/j.neuint.2025.105964

Ling Zhu , Congyan Liu , Yang Wang , Xuanang Zhu , Lei Wu , Lvan Chen , Jing Zhou , Fan Wang

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引用次数: 0

摘要

背景：小胶质细胞介导的神经炎症与阿尔茨海默病（AD）的发展密切相关。本研究进一步阐明了AD小胶质细胞极化的调控机制。方法：采用RT-qPCR、ELISA和免疫荧光（IF）检测小胶质细胞极化。Western blot （WB）分析炎症相关蛋白、p-tau蛋白和凋亡相关蛋白。免疫荧光法观察神经元损伤，流式细胞术和TUNEL法观察神经元凋亡。RT-qPCR和WB检测METTL3和IκBα的表达。用比色法测定n6 -甲基腺苷（m6A）水平。RNA下拉法检测METTL3、IGF2BP2和i - κ b α mRNA的结合。RT-qPCR检测IGF2BP的表达。采用morris水迷宫（MWM）测试和新目标识别（NOR）测试评价学习记忆能力。使用IF检测炎症相关蛋白。结果：Aβ1-42刺激导致小胶质细胞M1极化，炎症相关蛋白上调，神经元损伤和凋亡加剧，神经元中p-tau表达增加。METTL3/IGF2BP2通过结合i - κ b α mRNA调控i - κ b α m6A修饰，增强其表达。METTL3或IGF2BP2表达增强可抑制小胶质细胞M1极化、炎症和神经元凋亡，这一现象可通过下调IκBα而逆转。AD模型小鼠表现出认知障碍、神经炎症和M1极化升高。METTL3或IGF2BP2过表达可改善认知功能，减少神经炎症，抑制M1极化，这种作用同样可通过下调IκBα而逆转。结论：本研究提示METTL3/IGF2BP2/IκBα轴通过调节小胶质细胞M1/M2极化参与AD的神经炎症，为AD的治疗提供线索。

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METTL3/IGF2BP2/IκBα axis participates in neuroinflammation in Alzheimer's disease by regulating M1/M2 polarization of microglia

Background

Microglia-mediated neuroinflammation is closely related to the development of Alzheimer's disease (AD). This study further elucidated the regulatory mechanism of microglia polarization in AD.

Method

Microglia polarization was assessed using RT-qPCR, ELISA, and immunofluorescence (IF). Western blot (WB) analyzed inflammation-related, p-tau, and apoptosis-related proteins. Neuronal damage was evaluated by immunofluorescence, and neuronal apoptosis by flow cytometry and TUNEL assay. METTL3 and IκBα expression were detected using RT-qPCR and WB. N⁶-methyladenosine (m⁶A) levels were quantified with a colorimetric assay. RNA pull-down assay examined METTL3, IGF2BP2, and IκBα mRNA binding. IGF2BP expression was assessed by RT-qPCR. Learning and memory abilities were evaluated using morris water maze (MWM) test and novel object recognition (NOR) test. Inflammation-related proteins were detected using IF.

Results

Stimulation with Aβ_1-42 led to microglia M1 polarization, upregulation of inflammation-related proteins, and exacerbation of neuronal injury and apoptosis, along with increased p-tau expression in neurons. METTL3/IGF2BP2 modulated IκBα m⁶A modification through binding to IκBα mRNA, enhancing its expression. Enhanced METTL3 or IGF2BP2 expression suppressed M1 polarization, inflammation, and neuronal apoptosis in microglia, reversed by knockdown of IκBα. AD model mice exhibited cognitive impairments, neuroinflammation, and elevated M1 polarization. METTL3 or IGF2BP2 overexpression improved cognitive function, reduced neuroinflammation, and inhibited M1 polarization, and this effect was similarly reversed by knockdown of IκBα.

Conclusion

Our study demonstrates that the METTL3/IGF2BP2/IκBα axis is involved in neuroinflammation in AD by modulating microglia M1/M2 polarization, which sheds light on the treatment of AD.

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来源期刊

Neurochemistry international 医学-神经科学

CiteScore

8.40

自引率

2.40%

发文量

128

审稿时长

37 days

期刊介绍： Neurochemistry International is devoted to the rapid publication of outstanding original articles and timely reviews in neurochemistry. Manuscripts on a broad range of topics will be considered, including molecular and cellular neurochemistry, neuropharmacology and genetic aspects of CNS function, neuroimmunology, metabolism as well as the neurochemistry of neurological and psychiatric disorders of the CNS.