Interleukin-1 beta up-regulates TACE to enhance alpha-cleavage of APP in neurons: resulting decrease in Abeta production

J Neurochem. 2008 Mar;104(5):1387-93. doi: 10.1111/j.1471-4159.2007.05127.x. Epub 2007 Nov 16.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / biosynthesis*
  • ADAM Proteins / genetics
  • ADAM17 Protein
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Alzheimer Disease / therapy
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / biosynthesis
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Cell Line, Tumor
  • Cells, Cultured
  • Humans
  • Hydrolysis
  • Interleukin-1beta / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Neurons / metabolism*
  • Neurons / pathology
  • Up-Regulation / genetics
  • Up-Regulation / physiology*

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Interleukin-1beta
  • ADAM Proteins
  • ADAM17 Protein
  • ADAM17 protein, human
  • Adam17 protein, mouse