Abstract
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 P2X(7) 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, P2X(7) receptor was specifically up-regulated around beta-amyloid plaques in a mouse model of Alzheimer's disease (Tg2576).
Highlights
Activated microglia have been observed in patients suffering from both acute and chronic (Alzheimer’s disease) neurological disorders (1, 2)
Reactive oxygen intermediates (ROIs), one of several pro-inflammatory substances released by microglia (4), are likely to play a very important role in Alzheimer’s disease (AD) because hallmark modifications of ROI damage such as lipid peroxidation and nitrotyrosine conjugates are characteristic of post-mortem AD brains (3)
Generation of Reactive Oxygen Intermediates by Microglia— Primary rat microglia stimulated with ATP and BzATP rapidly generate ROIs, superoxide (O2.) in particular, measured indirectly as hydrogen peroxide (H2O2)
Summary
Activated microglia have been observed in patients suffering from both acute (stroke) and chronic (Alzheimer’s disease) neurological disorders (1, 2). Microglia are believed to contribute to the progression of Alzheimer’s disease (AD) because these cells can release pro-inflammatory substances known to induce neurotoxicity (3). Whereas the P2Y receptors are responsible for Ca2ϩ release predominantly from intracellular stores, P2X receptors are responsible for Ca2ϩ influx from extracellular sources. Oxidized ATP (oATP) is a specific antagonist of P2X7 that binds irreversibly to the receptor and prevents its activation by ATP (17). In this study, these pharmacological tools were used to determine the purinergic receptors involved in O2. Our studies elucidate a putative signal transduction pathway that mediates this response These studies demonstrate that BzATP- and ATP-activated microglia can mediate neurotoxicity. A distinct alteration was detected in the staining pattern for P2X7 receptor in a transgenic mouse model of AD, suggesting that P2X7 receptor activation could play a contributing role in AD
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