| First Author | Pan W | Year | 2026 |
| Journal | Sci Adv | Volume | 12 |
| Issue | 25 | Pages | eadz0887 |
| PubMed ID | 42319929 | Mgi Jnum | J:388020 |
| Mgi Id | MGI:8355000 | Doi | 10.1126/sciadv.adz0887 |
| Citation | Pan W, et al. (2026) Neuronal YTHDF2 suppresses innate immune activation in Abeta pathology by promoting m(6)A-dependent decay of cytosolic mitochondrial mRNAs. Sci Adv 12(25):eadz0887 |
| abstractText | Dysregulation of RNA m(6)A modification has been implicated in Alzheimer's disease (AD), but the molecular mechanisms remain largely unclear. Here, we identified the presence of m(6)A on mitochondria-encoded messenger RNAs (mt-mRNAs) in the brain, with elevated levels correlated with amyloid-beta (Abeta) deposition. Under physiological conditions, cytosolic m(6)A-modified mt-Nd4 is recognized and degraded by the m(6)A reader protein YTHDF2, thereby preventing aberrant activation of the RIG-I-MAVS innate immune pathway in neurons. Under Abeta-associated pathological conditions, YTHDF2 expression is markedly down-regulated in neurons, leading to the accumulation of m(6)A-modified mt-Nd4 in the cytosol. This accumulation triggers RIG-I-MAVS activation and type I interferon (IFN) responses. Neuron-derived IFN-beta then amplifies neuroinflammation by activating surrounding microglia through a paracrine mechanism. Furthermore, neuronal Ythdf2 deficiency exacerbates Abeta-associated neuroinflammation and cognitive decline. Together, these findings reveal a previously unrecognized m(6)A/YTHDF2-dependent regulatory axis that links mitochondrial RNA metabolism to innate immune activation and neuroinflammation in Abeta pathology. |
