P2X(7) receptor (P2X(7)R) is an ATP-gated cation channel that promotes microglia activation and plays a critical role in the pathogenesis of Alzheimer's disease. Inhibiting P2X(7)R indirectly reduces the rate of amyloid-beta (A beta)-induced neurodegeneration by suppressing secretion of inflammatory factors from activated microglia. We used RNA interference to silence P2X(7)R in microglial cells in vitro and found it markedly increased microglial phagocytosis of A beta(1-42). Increased phagocytic activity was dependent on decreasing the rate of interleukin-1 beta release from microglia and required inhibition of the COX-2 pathway. Modulation of microglial phagocytosis and secretion via silencing P2X(7)R may be a promising therapeutic option for the treatment of Alzheimer's disease. (C) 2013 Elsevier Inc. All rights reserved.