Neuronal YTHDF2 suppresses innate immune activation in Aβ pathology by promoting m⁶A-dependent decay of cytosolic mitochondrial mRNAs.

Authors

Wenqi Pan, Lin Yang, Yao Zhang, Yan Chen, Yuesi Xu, Yifan Li, Yujie Fu, Chunhui Ma, Chunying Liu, Qing Li, Hailong Liu, Hailin Wang, Qi Xu, Wei-Min Tong, Yamei Niu

Published in

Science advances. Volume 12. Issue 25. Pages eadz0887. Jun 19, 2026. Epub Jun 19, 2026.

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/YTHDF2-dependent regulatory axis that links mitochondrial RNA metabolism to innate immune activation and neuroinflammation in Aβ pathology.

PMID:
42319929
Bibliographic data and abstract were imported from PubMed on 20 Jun 2026.

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