P2X7 mediates superoxide production in primary microglia and is up-regulated in a transgenic mouse model of Alzheimer's disease

Abstract

Primary rat microglia stimulated with either ATP or 2′- and 3′-O-(4-benzoylbenzoyl)-ATP (BzATP) release copious amounts of superoxide (O2.-). ATP and BzATP stimulate O2.- production through purinergic receptors, primarily the P2X7 receptor. O2.- is produced through the activation of the NADPH oxidase. Although both p42/44 MAPK and p38 MAPK were activated rapidly in cells stimulated with BzATP, only pharmacological inhibition of p38 MAPK attenuated O2.- production. Furthermore, an inhibitor of phosphatidylinositol 3-kinase attenuated O2.- production to a greater extent than an inhibitor of p38 MAPK. Both ATP and BzATP stimulated microglia-induced cortical cell death indicating this pathway may contribute to neurodegeneration. Consistent with this hypothesis, P2X7 receptor was specifically up-regulated around β-amyloid plaques in a mouse model of Alzheimer's disease (Tg2576).