METTL3-dependent RNA m6A dysregulation contributes to neurodegeneration in Alzheimer\u2019s disease through aberrant cell cycle events

Fanpeng Zhao,Lixia Qin,Shichao Gao,Ying Xu,Beisha Tang,Sandra L Siedlak,Quillan Austria,Kinga Pajdzik,Xiongwei Zhu,James M O’Donnell,Qing Dai,Wenzhang Wang,Chuan He

doi:10.1186/s13024-021-00484-x

Abstract

BackgroundN6-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).MethodsWe 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.ResultsWe 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.ConclusionsCollectively, these data suggested that METTL3 reduction-mediated m6A dysregulation likely contributes to neurodegeneration in AD which may be a therapeutic target for AD.

Highlights

N6-methyladenosine (m6A) modification of RNA influences fundamental aspects of RNA metabolism and m6A dysregulation is implicated in various human diseases
Comparing to m6A immunostaining in age-matched control brains, the RNA m6A modification was significantly reduced in large pyramidal neurons in the Alzheimer disease (AD) brain (Fig. 1 A-F)
Inhibition of m6A demethylation reduces shMettl3induced deficits in primary neurons we investigated whether restoration of m6A modification by treatment of rhein, a natural product and small-molecule inhibitor of Fat mass and obesity associated protein (FTO) demethylase [60], could rescue methyltransferase like 3 (METTL3) depletion-induced reduced m6A modification and neuronal deficits

Summary

Introduction

N6-methyladenosine (m6A) modification of RNA influences fundamental aspects of RNA metabolism and m6A dysregulation is implicated in various human diseases. We explored the potential role of RNA m6A modification in the pathogenesis of Alzheimer disease (AD). Alzheimer’s disease (AD) is a degenerative brain disorder and the most prevalent form of dementia with progressive synaptic dysfunction, neuronal loss and memory. Zhao et al Molecular Neurodegeneration (2021) 16:70 incomplete understanding of pathogenic mechanisms underlying synaptic dysfunction, neuronal loss and memory deficits in AD. In addition to genetic studies, there are expanding number of studies on a potential role of epigenetic modifications in AD [5, 6]. These studies largely focused on epigenetic DNA modifications and provided important insights into the complex etiology of the late-onset AD. RNA m6A is deposited by a multicomponent methyltransferase complex consisting of methyltransferase like 3 (METTL3) [11], METTL14 [12, 13], and Wilms Tumor 1

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