title: Amyloid β oligomers induce interleukin-1β production in primary microglia in a cathepsin B- and reactive oxygen species-dependent manner.
abstract: Amyloid β (Aβ) peptide, a causative agent of Alzheimer's disease, forms two types of aggregates: oligomers and fibrils. These aggregates induce inflammatory responses, such as interleukin-1β (IL-1β) production by microglia, which are macrophage-like cells located in the brain. In this study, we examined the effect of the two forms of Aβ aggregates on IL-1β production in mouse primary microglia. We prepared Aβ oligomer and fibril from Aβ (1-42) peptide in vitro. We analyzed the characteristics of these oligomers and fibrils by electrophoresis and atomic force microscopy. Interestingly, Aβ oligomers but not Aβ monomers or fibrils induced robust IL-1β production in the presence of lipopolysaccharide. Moreover, Aβ oligomers induced endo/phagolysosome rupture, which released cathepsin B into the cytoplasm. Aβ oligomer-induced IL-1β 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-1β. Thus, multimerization and fibrillization causes Aβ oligomers to lose the ability to induce IL-1β. These results indicate that Aβ oligomers, but not fibrils, induce IL-1β production in primary microglia in a cathepsin B- and ROS-dependent manner.
authors: Department of Animal Development and Physiology, Kyoto University, Yoshida-Konoe, Sakyo, Kyoto 606-8501, Japan.
authors: Jun
authors: J
authors: Taneo
authors: Department of Animal Development and Physiology, Kyoto University, Yoshida-Konoe, Sakyo, Kyoto 606-8501, Japan.
authors: Takumi
authors: T
authors: Adachi
authors: Responses to Environmental Signals and Stresses, Graduate School of Biostudies, Kyoto University, Yoshida-Konoe, Sakyo, Kyoto, Kyoto 606-8501, Japan.
authors: Aiko
authors: A
authors: Yoshida
authors: Responses to Environmental Signals and Stresses, Graduate School of Biostudies, Kyoto University, Yoshida-Konoe, Sakyo, Kyoto, Kyoto 606-8501, Japan.
authors: Kunio
authors: K
authors: Takayasu
authors: Department of Animal Development and Physiology, Kyoto University, Yoshida-Konoe, Sakyo, Kyoto 606-8501, Japan; Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), Tokyo 102-0081, Japan. Electronic address: ktakahar@zoo.zool.kyoto-u.ac.jp.
authors: Kazuhiko
authors: K
authors: Takahara
authors: Department of Animal Development and Physiology, Kyoto University, Yoshida-Konoe, Sakyo, Kyoto 606-8501, Japan; Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), Tokyo 102-0081, Japan.
authors: Kayo
authors: K
authors: Inaba
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000276:immunology* / Q000648:ultrastructure; D000818:Animals; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000276:immunology*; D003432:Cross-Linking Reagents / Q000737:chemistry; D004151:Dipeptides / Q000494:pharmacology; D053583:Interleukin-1beta / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000187:drug effects / Q000276:immunology*; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology* / Q000648:ultrastructure; D017382:Reactive Oxygen Species / Q000276:immunology*
chemical_list: D016229:Amyloid beta-Peptides; D003432:Cross-Linking Reagents; D004151:Dipeptides; D053583:Interleukin-1beta; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); C068250:N-(3-propylcarbamoyloxirane-2-carbonyl)-isoleucyl-proline; D002401:Cathepsin B; D000111:Acetylcysteine
keywords: AFM; Amyloid β; Fibrils; IL-1β; Microglia; Oligomers