Abstract
Present study demonstrated that fibrillar beta-amyloid peptide (fAbeta1-42) induced ATP release, which in turn activated NADPH oxidase via the P2X7 receptor (P2X7R). Reactive oxygen species (ROS) production in fAbeta1-42- treated microglia appeared to require Ca2+ influx from extracellular sources, because ROS generation was abolished to control levels in the absence of extracellular Ca2+. Considering previous observation of superoxide generation by Ca2+ influx through P2X7R in microglia, we hypothesized that ROS production in fAbeta-stimulated microglia might be mediated by ATP released from the microglia. We therefore examined whether fAbeta1-42-induced Ca2+ influx was mediated through P2X7R activation. In serial experiments, we found that microglial pretreatment with the P2X7R antagonists Pyridoxal-phosphate-6-azophenyl-2',4'- disulfonate (100 microM) or oxidized ATP (100 microM) inhibited fAbeta-induced Ca2+ influx and reduced ROS generation to basal levels. Furthermore, ATP efflux from fAbeta1-42- stimulated microglia was observed, and apyrase treatment decreased the generation of ROS. These findings provide conclusive evidence that fAbeta-stimulated ROS generation in microglial cells is regulated by ATP released from the microglia in an autocrine manner.
Highlights
A neuropathological characteristic of Alzheimer's disease (AD) is the appearance of neuritic plaques consisting of extracellular beta-amyloid peptide (Aβ) surrounded by reactive microglial cells (Sastre et al, 2006)
These results indicate that reactive oxygen species (ROS) production in fAβ1-42-stimulated microglia is initiated slowly, and continues for a long period
The major new finding in this study is that fAβ1-42 induces ATP release from microglia and that ATP regulates ROS generation through the activation of P2X7 receptor (P2X7R) and Ca2+ influx
Summary
A neuropathological characteristic of Alzheimer's disease (AD) is the appearance of neuritic plaques consisting of extracellular beta-amyloid peptide (Aβ) surrounded by reactive microglial cells (Sastre et al, 2006). Activation of NADPH oxidase occurs when inflammatory stimuli bring about the phosphorylation of p47phox and p67phox, and GDP/GTP exchange on Rac, causing these proteins to translocate to the membrane, where they assemble with p22phox and gp91phox (DeLeo and Quinn, 1996). The translocation of both the p47phox and p67phox subunits from the cytosol to the membrane has been observed in AD brain and fAβ-stimulated microglial cells (Bianca et al, 1999; Shimohama et al, 2000). The mechanisms responsible for this fAβ-stimulated NADPH oxidase activation remain largely unknown
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