P2RX7 drives inflammatory microglia and pathogenic extracellular vesicle secretion in tauopathy.

Genetic loss of P2rx7 in PS19 tauopathy mice mitigates brain atrophy, tau accumulation, and cognitive impairment, and microglia-specific deletion suppresses tau propagation.

• Why it matters: The molecular steps linking P2RX7 to microglial activation and extracellular vesicle (EV)–mediated spread of tau are unclear, limiting therapeutic targeting in AD.
• What they did: In PS19 mice, P2rx7 disruption was tested genetically, and microglial programs were mapped by single-cell RNA sequencing to define a first-responding microglial state (FRM) with prominent P2rx7 expression.
• The result: P2RX7 drives FRM-to-inflammatory microglial transition and increases EV loading of tau and mitochondrial proteins/DNA, which triggers cytosolic DNA sensing and interferon signaling in recipient microglia and promotes neuronal endolysosomal disruption and endosomal tau escape.

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