Interleukin-1 beta up-regulates TACE to enhance alpha-cleavage of APP in neurons: resulting decrease in Abeta production |
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Authors: | Tachida Yuriko Nakagawa Kazuhiro Saito Takashi Saido Takaomi C Honda Takashi Saito Yuko Murayama Shigeo Endo Tamao Sakaguchi Gaku Kato Akira Kitazume Shinobu Hashimoto Yasuhiro |
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Affiliation: | Glyco-chain Functions Laboratory, Supra-biomolecular System Group, Frontier Research System, The Institute of Physical and Chemical Research (RIKEN), Saitama, Japan, and CREST, Japan Science and Technology Agency, Saitama, Japan; Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, Japan; Anatomy and Neuroscience, Division of Human Life Science, School of Nursing, Fukushima Medical University, Fukushima, Japan; Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan; The Glycobiology Research Group, Tokyo Metropolitan Institute of Gerontology, Foundation for Research on Aging and Promotion of Human Welfare, Tokyo, Japan; Pain and Neurology, Discovery Research Laboratories, Shionogi Co. Ltd., Shiga, Japan; Department of Biochemistry, School of Medicine, Fukushima Medical University, Fukushima, Japan |
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Abstract: | The proinflammatory cytokine interleukin (IL)-1β is up-regulated in microglial cells surrounding amyloid plaques, leading to the hypothesis that IL-1β is a risk factor for Alzheimer's disease. However, we unexpectedly found that IL-1β significantly enhanced α-cleavage, indicated by increases in sAPPα and C83, but reduced β-cleavage, indicated by decreases in sAPPβ and Aβ40/42, in human neuroblastoma SK-N-SH cells. IL-1β did not significantly alter the mRNA levels of BACE1, ADAM-9, and ADAM-10, but up-regulated that of TACE by threefold. The proform and mature form of TACE protein were also significantly up-regulated. A TACE inhibitor (TAPI-2) concomitantly reversed the IL-1β-dependent increase in sAPPα and decrease in sAPPβ, suggesting that APP consumption in the α-cleavage pathway reduced its consumption in the β-cleavage pathway. IL-1Ra, a physiological antagonist for the IL-1 receptor, reversed the effects of IL-1β, suggesting that the IL-1β-dependent up-regulation of α-cleavage is mediated by the IL-1 receptor. IL-1β also induced this concomitant increase in α-cleavage and decrease in β-cleavage in mouse primary cultured neurons. Taken together we conclude that IL-1β is an anti-amyloidogenic factor, and that enhancement of its signaling or inhibition of IL-1Ra activity could represent potential therapeutic strategies against Alzheimer's disease. |
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Keywords: | Alzheimer's disease Aβ IL-1Ra IL-1β sAPPα TACE |
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