Alzheimer's disease (AD) is characterized by the accumulation of extracellular amyloid-beta (A beta) fibrils with microglia. Recently, there has been great interest in the microglial phagocytosis of A beta, because the microglial pathway is considered to be one of the A beta clearance pathways in the brain parenchyma. However, the mechanism of microglial phagocytosis of A beta is not fully understood and, thus, was investigated in this study. At one minute after exposure to A beta(1-42) (A beta 42), A beta immunoreactivity was detected at the cell surface of microglia. After 1 h, marked immunoreactivity was observed in the cytosolic vesicles. At 12 h, delayed phagocytosis of fibrillar A beta 42 was also observed with the formation of a large phagocytic cup. The microglial cell shape rapidly changed to an ameboid form during the process of phagocytosis. Although neither neural Wiskott-Aldrich syndrome protein (N-WASP) nor WASP interacting SH3 protein (WISH) immunoreactivity was co-localized with filamentous actin (F-actin) distribution, both WASP family verprolin-homologous protein (WAVE) and Rac1 immunoreactivity was co-localized with F-actin in the lamellipodia of phogocytic microglia. These results suggest that WAVE and Rac1 participate in the phagocytosis of A beta 42 by microglia.