Mettl3 regulates the pathogenesis of Alzheimers disease via fine-tuning Lingo2 (PRJCA021560)
Alzheimers disease (AD) is the most common neurodegenerative disease, and diverse factors contribute to its pathogenesis. Previous studies have suggested the dysregulation of m6A modification in AD, but the underlying mechanism and targets remain largely unknown. In the present study, we have shown that the levels of Mettl3 and m6A are increased in the brains of 5xFAD mice and post-mortem AD patients, respectively. Heterozygous deletion of neuronal Mettl3 (AD;Mettl3+/-) reduced Aß plaques and inflammation, and improved learning and memory of AD mice, but Mettl3 knock in (AD;Mettl3-KI) mice exhibited exacerbated pathogenesis and behavioral deficits. Mechanistically, we observed that m6A modification of Lingo2 was read by YTHDF2 and enhanced mRNA degradation of Lingo2. The decreased level of Lingo2 enhanced the interaction between APP and Bace1, and subsequently increased Aß production, which can be inhibited by Mettl3 depletion. Both ectopic Lingo2 and the administration of Mettl3 inhibitor STM2457 significantly alleviated the pathological and behavioral deficits of AD mice. In summary, our study has revealed the important function of Mettl3 and m6A in the pathogenesis of AD and provided novel insight for the underlying mechanisms. Our study also suggests that m6A and Lingo2 could be potential targets for AD at clinic.