P2RX7 drives inflammatory microglia and pathogenic extracellular vesicle secretion in tauopathy

P2X purinoreceptor 7 (P2RX7), an ATP-gated ion channel, contributes to Alzheimer's disease (AD) progression, but its molecular mechanisms remain unclear. Here, we show that genetic disruption of P2rx7 mitigates brain atrophy, tau accumulation, and cognitive impairment in PS19 mice. Microglia-specific, but not astrocyte-specific, deletion of P2rx7 suppresses tau propagation. Single-cell RNA sequencing identifies a previously unrecognized first-responding microglial state (FRM) with prominent P2rx7 expression. P2RX7 promotes the transition from FRM to an inflammatory microglial state enriched in extracellular vesicle (EV) biogenesis. P2RX7 increases EV loading of tau and of mitochondrial proteins and DNA, which activate cytosolic DNA sensing and interferon signaling in recipient microglia. Tau-containing microglial EVs disrupt neuronal endolysosomal integrity and facilitate endosomal tau escape and phosphorylation. Thus, P2RX7 regulates the FRM branch point, driving inflammatory microglial transition and EV-mediated spread of tau and toxic mitochondrial molecules and highlighting the P2RX7-EV axis as a therapeutic target in AD.