P2X7 receptor-dependent microglia-astrocyte coupling in Alzheimer's disease: from eATP sensing to synaptic and...

Alzheimer's disease (AD) is characterized not only by amyloid-β and tau pathology but also by progressive failure of multicellular homeostasis. The P2X7 receptor (P2X7R), a low-affinity ATP-gated ion channel preferentially activated in extracellular ATP-rich pathological microenvironments, is well positioned to translate local tissue stress into sustained glial dysfunction. Although P2X7R has traditionally been studied as a microglial inflammasome-associated receptor, its broader significance may lie in coupling microglial activation to astrocytic loss of homeostatic support. In this review, we propose an integrative model in which P2X7R functions as a high-threshold inter-glial transducer through five interconnected axes: extracellular ATP amplification, cytokine relay, extracellular vesicle exchange, convergent synaptic modulation and circuit destabilization, and a coordinated clearance-to-retention switch. Microglial P2X7R activation promotes cytokine and reactive oxygen species production, vesicle and mitochondrial release, inflammatory reprogramming, and impaired phagocytic and lysosomal competence. Astrocytic P2X7R may reinforce this environment through feed-forward ATP release, altered gliotransmission, reactive transformation, extracellular vesicle shedding, and disrupted autophagic and lysosomal processing. We further situate this reciprocal loop within the amyloid plaque niche, where dystrophic neurites, stressed synapses, and reactive glia may create a spatially restricted P2X7R-sensitive ATP microdomain. The resulting cross-glial amplification is proposed to connect neuroinflammation with synaptic destabilization and defective proteostasis. This framework also suggests that brain-penetrant and pharmacologically selective P2X7R antagonists could complement protein-targeted therapies, particularly when guided by functional biomarkers of receptor activity. However, the proposed coupling architecture remains an integrative and testable hypothesis because much of the supporting evidence derives from non-AD models, in vitro studies, or correlative human tissue analyses. Cell-type-specific, temporally resolved studies are therefore required to establish whether P2X7R-dependent microglia-astrocyte coupling causally drives AD progression.