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

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

Molecular neurodegeneration (2021-10-02)
Fanpeng Zhao, Ying Xu, Shichao Gao, Lixia Qin, Quillan Austria, Sandra L Siedlak, Kinga Pajdzik, Qing Dai, Chuan He, Wenzhang Wang, James M O'Donnell, Beisha Tang, Xiongwei Zhu
ABSTRACT

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

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Deoxyribonuclease I from bovine pancreas, Type II-S, lyophilized powder, Protein ≥80 %, ≥2,000 units/mg protein
Sigma-Aldrich
Poly-D-lysine hydrobromide, mol wt 70,000-150,000, lyophilized powder, γ-irradiated, BioReagent, suitable for cell culture
Sigma-Aldrich
N-Acetyl-L-cysteine, Sigma Grade, ≥99% (TLC), powder
Sigma-Aldrich
Anti-Actin Antibody, clone C4, ascites fluid, clone C4, Chemicon®
Sigma-Aldrich
Anti-NeuN Antibody, clone A60, clone A60, Chemicon®, from mouse
Sigma-Aldrich
Cresyl Violet acetate, certified by the Biological Stain Commission
Sigma-Aldrich
Actinomycin D, from Streptomyces sp., ~98% (HPLC)
Sigma-Aldrich
Anti-Microtubule-Associated Protein 2 (MAP2) Antibody, Chemicon®, from rabbit
Sigma-Aldrich
Anti-METTL14 Antibody, from rabbit, purified by affinity chromatography
Sigma-Aldrich
Anti-FTO Antibody, clone 5-2H10, clone 5-2H10, from mouse