Exp Mol Med.  2007 Dec;39(6):820-827.

ATP released from beta-amyloid-stimulated microglia induces reactive oxygen species production in an autocrine fashion

• Kim SY
• Moon JH
• Lee HG
• Kim SU
• Lee YB

Abstract

Present study demonstrated that fibrillar beta-amyloid peptide (fAbeta(1-42)) induced ATP release, which in turn activated NADPH oxidase via the P2X(7) receptor (P2X(7)R). Reactive oxygen species (ROS) production in fAbeta(1-42)-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 P2X(7)R in microglia, we hypothesized that ROS production in fAbeta-stimulated microglia might be mediated by ATP released from the microglia. We therefore examined whether fAbeta(1-42)-induced Ca2+ influx was mediated through P2X(7)R activation. In serial experiments, we found that microglial pretreatment with the P2X(7)R antagonists Pyridoxal-phosphate-6-azophenyl-2',4'- disulfonate (100 micrometer) or oxidized ATP (100 micrometer) inhibited fAbeta-induced Ca2+ influx and reduced ROS generation to basal levels. Furthermore, ATP efflux from fAbeta(1-42)-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.

Keyword

adenosine triphosphate; Alzheimer's disease; amyloid beta-protein; calcium; microglia; NADPH oxidase; purinoceptor P2Z; reactive oxygen species

MeSH Terms

Adenosine Triphosphate/*metabolism
Amyloid beta-Protein/*pharmacology
Animals
Autocrine Communication/*drug effects/physiology
Cells, Cultured
Microglia/*drug effects
Peptide Fragments/*pharmacology
Pyridoxal Phosphate/analogs & derivatives/metabolism
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species/*metabolism
Receptors, Purinergic P2/physiology