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

Background: N6-methyladenosine (m⁶A) modification of RNA influences fundamental aspects of RNA metabolism and m⁶A dysregulation is implicated in various human diseases. In this study, we explored the potential role of RNA m⁶A modification in the pathogenesis of Alzheimer disease (AD). Methods: We investigated the m⁶A modification and the expression of m⁶A regulators in the brain tissues of AD patients and determined the impact and underlying mechanism of manipulated expression of m⁶A levels on AD-related deficits both in vitro and in vivo. Results: We found decreased neuronal m⁶A levels along with significantly reduced expression of m⁶A methyltransferase like 3 (METTL3) in AD brains. Interestingly, reduced neuronal m⁶A 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 m⁶A modification by inhibiting its demethylation in vitro rescued abnormal cell cycle events, neuronal deficits and death induced by METTL3 knockdown. Soluble Aβ oligomers caused reduced METTL3 expression and METTL3 knockdown exacerbated while METTL3 overexpression rescued Aβ-induced synaptic PSD95 loss in vitro. Importantly, METTL3 overexpression rescued Aβ-induced synaptic damage and cognitive impairment in vivo. Conclusions: Collectively, these data suggested that METTL3 reduction-mediated m⁶A dysregulation likely contributes to neurodegeneration in AD which may be a therapeutic target for AD. [ABSTRACT FROM AUTHOR]