METTL3-dependent RNA m6A dysregulation contributes to neurodegeneration in Alzheimer's disease through aberrant cell cycle events

Background N6-methyladenosine (m(6)A) modification of RNA influences fundamental aspects of RNA metabolism and m(6)A dysregulation is implicated in various human diseases. In this study, we explored the potential role of RNA m(6)A modification in the pathogenesis of Alzheimer disease (AD). Methods We investigated the m(6)A modification and the expression of m(6)A regulators in the brain tissues of AD patients and determined the impact and underlying mechanism of manipulated expression of m(6)A levels on AD-related deficits both in vitro and in vivo. Results We found decreased neuronal m(6)A levels along with significantly reduced expression of m(6)A methyltransferase like 3 (METTL3) in AD brains. Interestingly, reduced neuronal m(6)A modification in the hippocampus caused by METTL3 knockdown led to significant memory deficits, accompanied by extensive synaptic loss and neuronal death along with multiple AD-related cellular alterations including oxidative stress and aberrant cell cycle events in vivo. Inhibition of oxidative stress or cell cycle alleviated shMettl3-induced apoptotic activation and neuronal damage in primary neurons. Restored m(6)A modification by inhibiting its demethylation in vitro rescued abnormal cell cycle events, neuronal deficits and death induced by METTL3 knockdown. Soluble A beta oligomers caused reduced METTL3 expression and METTL3 knockdown exacerbated while METTL3 overexpression rescued A beta-induced synaptic PSD95 loss in vitro. Importantly, METTL3 overexpression rescued A beta-induced synaptic damage and cognitive impairment in vivo. Conclusions Collectively, these data suggested that METTL3 reduction-mediated m(6)A dysregulation likely contributes to neurodegeneration in AD which may be a therapeutic target for AD.

Automated summary

The study revealed that decreased m(6)A levels and reduced expression of METTL3 in AD brains led to memory deficits, synaptic loss, neuronal death, and multiple cellular alterations. Restoring m(6)A modification by inhibiting demethylation or overexpressing METTL3 rescued synaptic damage, cognitive impairment, and neuronal deficits in AD models.