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

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 <i>mt-Nd4</i> 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 <i>mt-Nd4</i> 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 <i>Ythdf2</i> 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.