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 in mon...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2023-03-01
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| Series: | PLoS Biology |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9990945/?tool=EBI |
| _version_ | 1811155394888728576 |
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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. This study reveals that loss of METTL3, and the corresponding changes in m6A modifications, leads to enhanced brain infiltration of monocyte-derived macrophages in a mouse model of Alzheimer’s Disease, promoting Aβ clearance and ameliorating pathology and cognitive decline. |
| first_indexed | 2024-04-10T04:33:30Z |
| format | Article |
| id | doaj.art-0477d856b35e489fb87359eb8d129882 |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-04-10T04:33:30Z |
| publishDate | 2023-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-0477d856b35e489fb87359eb8d1298822023-03-10T05:31:13ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852023-03-01213Loss of the m6A methyltransferase METTL3 in monocyte-derived macrophages ameliorates Alzheimer’s disease pathology in miceHuilong 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. This study reveals that loss of METTL3, and the corresponding changes in m6A modifications, leads to enhanced brain infiltration of monocyte-derived macrophages in a mouse model of Alzheimer’s Disease, promoting Aβ clearance and ameliorating pathology and cognitive decline.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9990945/?tool=EBI |
| 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://www.ncbi.nlm.nih.gov/pmc/articles/PMC9990945/?tool=EBI |
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