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

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 i...

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Main Authors: Huilong Yin, Zhuan Ju, Minhua Zheng, Xiang Zhang, Wenjie Zuo, Yidi Wang, Xiaochen Ding, Xiaofang Zhang, Yingran Peng, Jiadi Li, Angang Yang, Rui Zhang
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2023-03-01
Series:PLoS Biology
Online Access:https://doi.org/10.1371/journal.pbio.3002017
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author Huilong Yin
Zhuan Ju
Minhua Zheng
Xiang Zhang
Wenjie Zuo
Yidi Wang
Xiaochen Ding
Xiaofang Zhang
Yingran Peng
Jiadi Li
Angang Yang
Rui Zhang
author_facet Huilong Yin
Zhuan Ju
Minhua Zheng
Xiang Zhang
Wenjie Zuo
Yidi Wang
Xiaochen Ding
Xiaofang Zhang
Yingran Peng
Jiadi Li
Angang Yang
Rui Zhang
author_sort Huilong Yin
collection DOAJ
description 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.
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spelling doaj.art-4526e8330c154eafbd02f5408613b99f2023-04-12T05:30:43ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852023-03-01213e300201710.1371/journal.pbio.3002017Loss of the m6A methyltransferase METTL3 in monocyte-derived macrophages ameliorates Alzheimer's disease pathology in mice.Huilong YinZhuan JuMinhua ZhengXiang ZhangWenjie ZuoYidi WangXiaochen DingXiaofang ZhangYingran PengJiadi LiAngang YangRui ZhangAlzheimer'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.https://doi.org/10.1371/journal.pbio.3002017
spellingShingle Huilong Yin
Zhuan Ju
Minhua Zheng
Xiang Zhang
Wenjie Zuo
Yidi Wang
Xiaochen Ding
Xiaofang Zhang
Yingran Peng
Jiadi Li
Angang Yang
Rui Zhang
Loss of the m6A methyltransferase METTL3 in monocyte-derived macrophages ameliorates Alzheimer's disease pathology in mice.
PLoS Biology
title Loss of the m6A methyltransferase METTL3 in monocyte-derived macrophages ameliorates Alzheimer's disease pathology in mice.
title_full Loss of the m6A methyltransferase METTL3 in monocyte-derived macrophages ameliorates Alzheimer's disease pathology in mice.
title_fullStr Loss of the m6A methyltransferase METTL3 in monocyte-derived macrophages ameliorates Alzheimer's disease pathology in mice.
title_full_unstemmed Loss of the m6A methyltransferase METTL3 in monocyte-derived macrophages ameliorates Alzheimer's disease pathology in mice.
title_short Loss of the m6A methyltransferase METTL3 in monocyte-derived macrophages ameliorates Alzheimer's disease pathology in mice.
title_sort loss of the m6a methyltransferase mettl3 in monocyte derived macrophages ameliorates alzheimer s disease pathology in mice
url https://doi.org/10.1371/journal.pbio.3002017
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