Mettl3 regulates the pathogenesis of Alzheimer’s disease via fine-tuning Lingo2

Alzheimer’s disease (AD) is the most common neurodegenerative disease, and diverse factors contribute to its pathogenesis. Previous studies have suggested the dysregulation of m⁶A modification involves 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 modification are increased in specific brain regions of 5xFAD mice and post-mortem AD patients, respectively. Heterozygous deletion of neuronal Mettl3 (AD::Mettl3^+/−) reduced Aβ plaques and inflammation, and improved learning and memory of AD mice, and vice versa for Mettl3 knock in (AD::Mettl3-KI). Mechanistically, we observed that the level of m⁶A modification of Lingo2 increased in 5xFAD mice and AD patients, which promoted the binding of Ythdf2 and enhanced the degradation of Lingo2 mRNA. The decreased level of Lingo2 promoted the interaction between APP and β-site amyloid precursor protein cleaving enzyme (Bace1), and subsequently enhanced Aβ production in AD mice, which can be inhibited by Mettl3 depletion. Both ectopic Lingo2 and the administration of Mettl3 inhibitor STM2457 significantly alleviated the neuropathology 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 therapeutic targets for AD.