P2X7 Mediates Superoxide Production in Primary Microglia and Is Up-regulated in a Transgenic Mouse Model of Alzheimer's Disease*

Primary rat microglia stimulated with either ATP or 2′- and 3′-O-(4-benzoylbenzoyl)-ATP (BzATP) release copious amounts of superoxide (O 2 ⨪ ). ATP and BzATP stimulate O 2 ⨪ production through purinergic receptors, primarily the P2X7 receptor. O 2 ⨪ 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 O 2 ⨪ production. Furthermore, an inhibitor of phosphatidylinositol 3-kinase attenuated O 2 ⨪ 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).

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