The extracellular ATP/P2X7R signaling axis drives early neuroinflammation and neuronal hyperexcitability in an Alzheimer’s disease mouse model

Neuroinflammation and synaptic dysfunction are emerging as early and potentially causative events in Alzheimer’s disease (AD), yet their molecular triggers remain elusive. Here, we identify extracellular ATP (eATP), a major damage-associated molecular pattern, and its purinergic receptor P2X7 (P2X7R) as pivotal drivers of early pathology in AD mice. In vivo bioluminescence imaging revealed a significant cortical accumulation of eATP in AD mice as early as 2 months of age—before amyloid plaque deposition and cognitive impairment. This increase is associated with inflammasome activation, pro-inflammatory cytokine production, microglia reactivity, aberrant synaptic pruning and perineuronal net degradation. Strikingly, genetic deletion of P2X7R rescues these alterations. Two-photon calcium imaging further demonstrates that P2X7R knockout counteracts AD-related neuronal hyperactivity. These findings set the eATP–P2X7R signaling axis as an early driver of AD pathology, linking neuroinflammation to synaptic remodeling and circuit dysfunction, and suggest P2X7R inhibition as a compelling strategy to counteract AD progression.