Interleukin-1 beta up-regulates TACE to enhance alpha-cleavage of APP in neurons: resulting decrease in Abeta production.
The proinflammatory cytokine interleukin (IL)-1beta is up-regulated in microglial cells surrounding amyloid plaques, leading to the hypothesis that IL-1beta is a risk factor for Alzheimer's disease. However, we unexpectedly found that IL-1beta significantly enhanced alpha-cleavage, indicated by increases in sAPPalpha and C83, but reduced beta-cleavage, indicated by decreases in sAPPbeta and Abeta40/42, in human neuroblastoma SK-N-SH cells. IL-1beta 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-1beta-dependent increase in sAPPalpha and decrease in sAPPbeta, suggesting that APP consumption in the alpha-cleavage pathway reduced its consumption in the beta-cleavage pathway. IL-1Ra, a physiological antagonist for the IL-1 receptor, reversed the effects of IL-1beta, suggesting that the IL-1beta-dependent up-regulation of alpha-cleavage is mediated by the IL-1 receptor. IL-1beta also induced this concomitant increase in alpha-cleavage and decrease in beta-cleavage in mouse primary cultured neurons. Taken together we conclude that IL-1beta 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.
Tachida
Yuriko
Y
Glyco-chain Functions Laboratory, Supra-biomolecular System Group, Frontier Research System, The Institute of Physical and Chemical Research (RIKEN), Saitama, Japan.
Nakagawa
Kazuhiro
K
Saito
Takashi
T
Saido
Takaomi C
TC
Honda
Takashi
T
Saito
Yuko
Y
Murayama
Shigeo
S
Endo
Tamao
T
Sakaguchi
Gaku
G
Kato
Akira
A
Kitazume
Shinobu
S
Hashimoto
Yasuhiro
Y
D051722:ADAM Proteins / Q000096:biosynthesis* / Q000235:genetics; D000072198:ADAM17 Protein; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006801:Humans; D006868:Hydrolysis; D053583:Interleukin-1beta / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053583:Interleukin-1beta; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse