Loss of the m6A methyltransferase METTL3 in monocyte-derived macrophages ameliorates Alzheimer’s disease pathology in mice

Abstract

Alzheimer’s disease (AD) is a heterogeneous disease with complex clinicopathological characteristics. To date, the role of m6A RNA methylation in monocyte-derived macrophages involved in the progression of AD is unknown. In our study, we found that methyltransferase-like 3 (METTL3) deficiency in monocyte-derived macrophages improved cognitive function in an amyloid beta (Aβ)-induced AD mouse model. The mechanistic study showed that that METTL3 ablation attenuated the m6A modification in DNA methyltransferase 3A (Dnmt3a) mRNAs and consequently impaired YTH N6-methyladenosine RNA binding protein 1 (YTHDF1)-mediated translation of DNMT3A. We identified that DNMT3A bound to the promoter region of alpha-tubulin acetyltransferase 1 (Atat1) and maintained its expression. METTL3 depletion resulted in the down-regulation of ATAT1, reduced acetylation of α-tubulin and subsequently enhanced migration of monocyte-derived macrophages and Aβ clearance, which led to the alleviated symptoms of AD. Collectively, our findings demonstrate that m6A methylation could be a promising target for the treatment of AD in the future.

Accumulation of m6A exhibits stronger correlation with MAPT than β-amyloid pathology in an APPNL-G-F/MAPTP301Smouse model of Alzheimer’s disease

“…Such results are consistent with emerging studies showing that m 6 A regulates inflammation, macrophages and also astrocytosis [57][58][59][60][61]. Such findings raise the possibility that m 6 A modulation might also be applied towards regulation of inflammation in AD; indeed a recent study observed that conditional knockout of METTL3 in microglia attenuated inflammation and A accumulation in a mouse model based on A injection [62].…”

The Regulatory Network of METTL3 in the Nervous System: Diagnostic Biomarkers and Therapeutic Targets

“…These findings indicate that the aberrant expression and distribution of METTL3 in the hippocampus of the AD brain may represent an epi transcriptomic mechanism for the pathogenesis of AD [ 46 ]. Similarly, Yin et al reported that METTL3 downregulation in monocyte-derived macrophages improved cognitive function in an amyloid beta (Aβ)-induced AD mouse model [ 47 ]. Mechanistically, METTL3 downregulation reduced m6A modification in DNA methyltransferase 3A (DNMT3A) mRNAs and consistently inhibited YTHDF1-mediated DNMT3A translation.…”

“…Mechanistically, METTL3 downregulation reduced m6A modification in DNA methyltransferase 3A (DNMT3A) mRNAs and consistently inhibited YTHDF1-mediated DNMT3A translation. In addition, DNMT3A bound to the promoter region of alpha-tubulin acetyltransferase 1 (ATAT1) and maintained its expression [ 47 ]. Therefore, METTL3 depletion resulted in the downregulation of ATAT1, reduced acetylation of α-tubulin, and subsequently enhanced migration of monocyte-derived macrophages and Aβ clearance [ 47 ].…”

“…In addition, DNMT3A bound to the promoter region of alpha-tubulin acetyltransferase 1 (ATAT1) and maintained its expression [ 47 ]. Therefore, METTL3 depletion resulted in the downregulation of ATAT1, reduced acetylation of α-tubulin, and subsequently enhanced migration of monocyte-derived macrophages and Aβ clearance [ 47 ]. Collectively, these findings provide a novel METTL3/YTHDF1-DNMT3A-ATAT1 pathway for alleviating AD symptoms, suggesting that MEETL3 may also be a promising target for the future treatment of AD.…”

N6-Methyladenosine (m6A) Modification in Natural Immune Cell-Mediated Inflammatory Diseases

“…Defective METTL3 in blood-derived macrophages reduced DNA methyltransferase 3A ( Dnmt3a ) translation in a YTHDF1-dependent manner, downregulating α-tubulin acetylation due to decreased α-tubulin acetyltransferase 1 ( Atat1 ) expression. METTL3 deficiency improved cognitive function in an amyloid β (Aβ)-induced Alzheimer’s disease mouse model by enhancing macrophage migration and Aβ clearance [54].…”