In Alzheimer's disease, fibrillar amyloid-beta (Abeta) peptides form senile plaques associated with microglia. However, the relationship between Abeta peptides and microglia is not fully understood. In this study, the incubation of Abeta1-40 (Abeta40) produced small oligomers, while incubation with Abeta1-42 (Abeta42) caused large molecular aggregates. Microglial production of nitrite, interleukin-6 and tumor necrosis factor-alpha was induced by Abeta40, but not Abeta42. This production was significantly reduced by 15-deoxy-Delta(12,14) prostaglandin J(2), and it was completely suppressed by beta-sheet breaker peptide, Leu-Pro-Phe-Phe-Asp. These results suggest that small oligomers, rather than large molecular aggregates, mediate microglial activation induced by Abeta peptides.