The expression of the purinergic receptor subtype P2X(7)R, a nonselective cationic channel activated by high levels of adenosine triphosphate (ATP), has been studied in adult microglia obtained from Alzheimer disease (AD) and nondemented (ND) brains, in fetal human microglia exposed to Abeta(1-42) peptide and in vivo in Abeta(1-42)-injected rat hippocampus. Semiquantitative reverse transcriptase-polymerase chain reaction showed enhanced expression (increase of 70%) of P2X(7)R in AD microglia compared with ND cells (analysis of 6 AD and 8 ND cases). Immunohistochemical analysis showed prominent P2X(7)R expression in association with Abeta plaques and localized to HLA-DR-immunoreactive microglia. In cultured fetal human microglia, cells exposed to Abeta(1-42) (5 microM for 18 hours) had significantly elevated levels of P2X(7)R (by 106%) compared with untreated cells. Amplitudes of Ca(2+) responses in these cells, induced by the selective P2X(7)R agonist BzATP, were increased by 145% with Abeta(1-42) pretreatment relative to control (no peptide pretreatment) and were largely blocked if the P2X(7)R inhibitor-oxidized ATP (oxATP) was added with peptide in pretreatment solution. In vivo, double immunostaining analysis showed considerable P2X(7)R colocalized with microglia after injection of Abeta(1-42) (1 nmol) into rat hippocampus. The overall results suggest roles of P2X(7)R in mediating microglial purinergic inflammatory responses in AD brain.