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METTL14/m6A/CEBPD轴:在慢性大脑低输液相关的神经炎症中的关键参与者

Huanhuan Wang¹, Hanshu Zhao¹, Jiadi Gao¹

¹Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin, P. R. China.

Free radical biology & medicine

|March 6, 2026

概括

准METTL14可以减少神经炎症和血管痴呆症的认知衰退. 这种表观遗传方法通过稳定CEBPDmRNA来抑制微质M1极化,为这种情况提供了潜在的治疗方法.

科学领域:

神经科学是一个神经科学.
表观遗传学在表观遗传学中,表观遗传学是指表观遗传学.
分子生物学分子生物学

背景情况:

血管痴呆症 (VaD) 涉及由于慢性大脑低 perfusion (CCH) 和神经炎症而导致的认知衰退.
微质M1极化是CCH相关神经炎症的关键驱动因素,但其表观遗传调节尚未完全理解.
N6-甲基氨酸 (m6A) 修饰,特别是涉及METTL14,以及CCAAT增强剂结合蛋白三角 (CEBPD) 都与大脑炎症有关.

研究的目的:

研究METTL14在微质极化中的作用及其对慢性大脑低 perfusion (CCH) 病理学的影响.
阐明METTL14影响神经炎症和血管痴呆症 (VaD) 认知功能的表观遗传机制.

主要方法:

在体外研究中,使用用LPS/TNF-α治疗的HMC3细胞来评估METTL14和CEBPD表达和微质极化.
在体内研究使用双边常见动脉阻塞 (BCCAo) 诱导的CCH大鼠模型.
短发针RNA (shRNA) 和腺相关病毒 (AAV) 介导的METTL14的淘汰.
RNA免疫沉降PCR (RIP-PCR) 和m6A特异性免疫沉降PCR (MeRIP-qPCR) 来确认m6A的修饰和mRNA的稳定性.
使用空间学习和记忆和对象识别测试评估认知功能.

主要成果:

METTL14 knockdown抑制了HMC3细胞中LPS/TNF-α诱导的M1极化,减少了促炎因素和NF-κB激活.
在CCH大鼠中,海马METTL14和CEBPD水平升高.
在CCH大鼠中AAV介导的METTL14敲击减轻了神经炎症,神经元亡,并改善了认知缺陷.
证实METTL14通过m6A修饰来增强CEPDmRNA稳定性,而CEPD则作为下游调解剂.

结论:

通过通过m6A修饰损害CEPDmRNA稳定性,METTL14敲击抑制了CCH中的微质M1极化和神经炎症.
这一过程涉及TLR4/MyD88/NF-κB通路,导致血管痴呆症认知障碍的缓解.
METTL14代表了血管痴呆症的潜在表观遗传治疗点.

关键词:

这种CCAAT增强剂与三角形蛋白结合.慢性大脑低 perfusion 的时间.甲基转移酶类似的14 微质的极化是微质的极化 m6A 修改的修改

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