Neuronal YTHDF2 suppresses innate immune activation in Aβ pathology by promoting m<sup>6</sup>A-dependent decay of cytosolic mitochondrial mRNAs.
Overview
- Department of Pathology, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
- Center for Experimental Animal Research, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
Abstract
Dysregulation of RNA m6A modification has been implicated in Alzheimer’s disease (AD), but the molecular mechanisms remain largely unclear. Here, we identified the presence of m6A on mitochondria-encoded messenger RNAs (mt-mRNAs) in the brain, with elevated levels correlated with amyloid-β (Aβ) deposition. Under physiological conditions, cytosolic m6A-modified mt-Nd4 is recognized and degraded by the m6A reader protein YTHDF2, thereby preventing aberrant activation of the RIG-I–MAVS innate immune pathway in neurons. Under Aβ-associated pathological conditions, YTHDF2 expression is markedly down-regulated in neurons, leading to the accumulation of m6A-modified mt-Nd4 in the cytosol. This accumulation triggers RIG-I–MAVS activation and type I interferon (IFN) responses. Neuron-derived IFN-β then amplifies neuroinflammation by activating surrounding microglia through a paracrine mechanism. Furthermore, neuronal Ythdf2 deficiency exacerbates Aβ-associated neuroinflammation and cognitive decline. Together, these findings reveal a previously unrecognized m6A/
Reproduced under the paper's license (CC BY-NC), from the paper cited above.
Code
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Data
Datasets cited
- geo:GSE266459, at NCBI GEO; found in the text, “RNA-seq analysis”
Data, code, and materials availability
All data and code needed to evaluate and reproduce the results in the paper are present in the paper and/
Reproduced under the paper's license (CC BY-NC), from the paper cited above.
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 15 authors, 17 MeSH terms, 81 references.
Cite
This paper
Pan, W., Yang, L., Zhang, Y., Chen, Y., Xu, Y., Li, Y., Fu, Y., Ma, C., Liu, C., Li, Q., Liu, H., Wang, H., Xu, Q., Tong, W.-M., & Niu, Y. (2026). Neuronal YTHDF2 suppresses innate immune activation in Aβ pathology by promoting m&
BibTeX
@article{pan2026neuronal
author = {Pan, Wenqi and Yang, Lin and Zhang, Yao and Chen, Yan and Xu, Yuesi and Li, Yifan and Fu, Yujie and Ma, Chunhui and Liu, Chunying and Li, Qing and Liu, Hailong and Wang, Hailin and Xu, Qi and Tong, Wei-Min and Niu, Yamei},
title = {{Neuronal YTHDF2 suppresses innate immune activation in Aβ pathology by promoting m\&
journal = {Science advances},
year = {2026},
month = jun,
volume = {12},
number = {25},
pages = {eadz0887},
publisher = {American Association for the Advancement of Science},
issn = {2375-2548},
doi = {10.1126/
url = {https://
pmid = {42319929},
pmcid = {PMC13281811}
}
RIS
TY - JOUR
AU - Pan, Wenqi
AU - Yang, Lin
AU - Zhang, Yao
AU - Chen, Yan
AU - Xu, Yuesi
AU - Li, Yifan
AU - Fu, Yujie
AU - Ma, Chunhui
AU - Liu, Chunying
AU - Li, Qing
AU - Liu, Hailong
AU - Wang, Hailin
AU - Xu, Qi
AU - Tong, Wei-Min
AU - Niu, Yamei
TI - Neuronal YTHDF2 suppresses innate immune activation in Aβ pathology by promoting m&
T2 - Science advances
J2 - Sci Adv
PY - 2026
DA - 2026/
VL - 12
IS - 25
SP - eadz0887
SN - 2375-2548
PB - American Association for the Advancement of Science
DO - 10.1126/
UR - https://
LA - en
ER -
CSL-JSON
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