Xu Chenhaoyi, Huang Huanghuang, Zhang Min, Zhang Pei, Li Zezhi, Liu Xueyuan, Fang Min
Department of Neurology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China.
Front Aging Neurosci. 2022 Apr 25;14:890134. doi: 10.3389/fnagi.2022.890134. eCollection 2022.
Activity-regulated cytoskeleton-associated protein (ARC) is activated by the induction of long-term potentiation and plays an important role in the synaptic plasticity of memory consolidation. Previous studies have shown that abnormal expression of ARC in the brains of patients with Alzheimer's Disease (AD) leads to the disturbance of synaptic plasticity. ARC expression is mainly regulated by transcriptional and post-translational modification. However, it is unclear whether N6-methyladenosine (mA) engages in the epigenetic modification of . The AlzData database was used to analyze the brain of AD patients, and Aβ-induced cell models were used. We revealed that ARC expression was reduced in AD patients and Aβ-induced cell models. There were five mA modification sites of mRNA that were predicted by the SRAMP database, and mRNA was confirmed as the target gene of methyltransferase-like 3 (METTL3) by MeRIP. Amyloid-beta protein (Aβ) repressed the mA modification. Knockdown of METTL3 decreased mRNA mA modification and reduced ARC protein expression, while overexpression of METTL3 rescued ARC expression after Aβ treatment. Knockdown of YTH domain family, member 1 (YTHDF1) decreased ARC protein expression, while the overexpression of YTHDF1 could not rescue the loss of ARC protein expression after 3-deazaadenosine treatment or knockdown of METTL3. Our findings identify that METTL3 rescues the Aβ-induced reduction of ARC expression YTHDF1-Dependent mA modification, which suggests an important mechanism of epigenetic alteration in AD.
活性调节细胞骨架相关蛋白（ARC）通过长期增强作用的诱导而被激活，并在记忆巩固的突触可塑性中发挥重要作用。先前的研究表明，阿尔茨海默病（AD）患者大脑中ARC的异常表达会导致突触可塑性紊乱。ARC的表达主要受转录和翻译后修饰的调控。然而，尚不清楚N6-甲基腺苷（m6A）是否参与了ARC的表观遗传修饰。我们使用AlzData数据库分析AD患者的大脑，并构建了Aβ诱导的细胞模型。我们发现，AD患者和Aβ诱导的细胞模型中ARC表达降低。SRAMP数据库预测ARC mRNA有5个m6A修饰位点，MeRIP证实ARC mRNA是甲基转移酶样3（METTL3）的靶基因。淀粉样β蛋白（Aβ）抑制m6A修饰。敲低METTL3会降低ARC mRNA的m6A修饰并减少ARC蛋白表达，而METTL3的过表达可在Aβ处理后挽救ARC表达。敲低YTH结构域家族成员1（YTHDF1）会降低ARC蛋白表达，而YTHDF1的过表达不能挽救3-脱氮腺苷处理或敲低METTL3后ARC蛋白表达的缺失。我们的研究结果表明，METTL3通过依赖YTHDF1的m6A修饰挽救了Aβ诱导的ARC表达降低，这提示了AD表观遗传改变的一个重要机制。
