Targeting the P2X7 receptor in Alzheimer's disease: mechanistic insights and emerging therapeutic strategies.

Abstract

Alzheimer's disease (AD) is the most common cause of dementia worldwide and is characterized by progressive cognitive decline, amyloid-β deposition, tau pathology, neuroinflammation, and neuronal loss. Current therapies provide only limited symptomatic benefit, and although anti-amyloid monoclonal antibodies have demonstrated disease-modifying potential in selected patients, additional disease-modifying targets are still needed. The purinergic P2X7 receptor (P2X7R), an ATP-gated ion channel predominantly expressed on microglia and astrocytes, has emerged as a key regulator of neuroinflammatory signalling and AD progression. This narrative review summarizes and critically discusses recent preclinical, translational, and clinical evidence published through 2026. Evidence from cellular and animal models, post-mortem human brain analyses, positron emission tomography (PET) imaging studies, and pharmacological investigations was evaluated to assess the role of P2X7R in AD pathogenesis and therapeutic intervention. Accumulating evidence demonstrates that extracellular ATP-mediated activation of P2X7R promotes NLRP3 inflammasome assembly, caspase-1 activation, and the release of pro-inflammatory cytokines, including interleukin-1β and interleukin-18, thereby sustaining chronic neuroinflammation. Genetic deletion or pharmacological inhibition of P2X7R reduced amyloid plaque burden, attenuated tau hyperphosphorylation, improved synaptic function, and ameliorated cognitive deficits in experimental AD models. Human studies further revealed elevated P2X7R expression and increased neuroinflammatory activity associated with AD pathology. Emerging therapeutic approaches include selective P2X7R antagonists, natural-product modulators, RNA-based interventions, nanotechnology-assisted drug delivery systems, and combination therapies targeting multiple pathogenic pathways. P2X7R represents a promising candidate target for disease-modifying therapeutic strategies in AD, based on convergent in vitro, animal-model, human post-mortem, and imaging/biomarker evidence linking ATP-mediated danger signalling to neuroinflammation, amyloid and tau pathology, and neurodegeneration. However, its clinical efficacy in AD remains to be established, as no clinical trial data for P2X7R-targeted therapies in this disease are yet available. Future clinical translation will require improved CNS-penetrant antagonists, enhanced receptor selectivity, biomarker-guided patient stratification, and precision medicine approaches.