Amyloid beta (A beta) peptide, a causative agent of Alzheimer's disease, forms two types of aggregates: oligomers and fibrils. These aggregates induce inflammatory responses, such as interleukin-1 beta (IL-1 beta) production by microglia, which are macrophage-like cells located in the brain. In this study, we examined the effect of the two forms of A beta aggregates on IL-1 beta production in mouse primary microglia. We prepared A beta oligomer and fibril from A beta (1-42) peptide in vitro. We analyzed the characteristics of these oligomers and fibrils by electrophoresis and atomic force microscopy. Interestingly, A beta oligomers but not A beta monomers or fibrils induced robust IL-1 beta production in the presence of lipopolysaccharide. Moreover, A beta oligomers induced endo/phagolysosome rupture, which released cathepsin B into the cytoplasm. A beta oligomer-induced IL-1 beta production was inhibited not only by the cathepsin B inhibitor CA-074-Me but also by the reactive oxygen species (ROS) inhibitor N-acetylcysteine. Random chemical crosslinking abolished the ability of the oligomers to induce IL-1 beta. Thus, multimerization and fibrillization causes A beta oligomers to lose the ability to induce IL-1 beta. These results indicate that A beta oligomers, but not fibrils, induce IL-1 beta production in primary microglia in a cathepsin B- and ROS-dependent manner. (C) 2015 Elsevier Inc. All rights reserved.