Constitutive shedding of the amyloid precursor protein ectodomain is up-regulated by tumour necrosis factor-alpha converting enzyme

Biochem J. 2001 Aug 1;357(Pt 3):787-94. doi: 10.1042/0264-6021:3570787.


The amyloid precursor protein (APP) of Alzheimer's disease is a transmembrane protein that is cleaved within its extracellular domain, liberating a soluble N-terminal fragment (sAPP alpha). Putative mediators of this process include three members of the ADAM (a disintegrin and metalloprotease) family, ADAM9, ADAM10 and ADAM17/TACE (tumour necrosis factor-alpha converting enzyme). Tumour necrosis factor-alpha protease inhibitor (TAPI-1), an inhibitor of ADAMs, reduced constitutive and muscarinic receptor-stimulated sAPP alpha release in HEK-293 cells stably expressing M3 muscarinic receptors. However, the former was less sensitive to TAPI-1 (IC(50)=8.09 microM) than the latter (IC(50)=3.61 microM), suggesting that these processes may be mediated by different metalloproteases. Constitutive sAPP alpha release was increased several-fold in cells transiently transfected with TACE, and this increase was proportional to TACE expression. In contrast, muscarinic-receptor-activated sAPP alpha release was not altered in TACE transfectants. TACE-dependent constitutive release of co-transfected APP(695) was inhibited by TAPI-1 with an IC(50) of 0.92 microm, a value significantly lower than the IC(50)s for inhibition of either constitutive or receptor-regulated sAPP alpha shedding mediated by endogenous secretases. The results indicate that TACE is capable of catalysing constitutive alpha-secretory cleavage of APP, but it is likely that additional members of the ADAM family mediate endogenous constitutive and receptor-coupled release of sAPP alpha in HEK-293 cells.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ADAM Proteins
  • ADAM17 Protein
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Protein Precursor / chemistry
  • Amyloid beta-Protein Precursor / metabolism*
  • Aspartic Acid Endopeptidases
  • Cells, Cultured
  • Dipeptides / pharmacology
  • Endopeptidases / metabolism
  • Humans
  • Hydroxamic Acids / pharmacology
  • Metalloendopeptidases / antagonists & inhibitors
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism*
  • Protease Inhibitors / pharmacology
  • Protein Structure, Tertiary
  • Receptor, Muscarinic M3
  • Receptors, Muscarinic / genetics
  • Receptors, Muscarinic / metabolism
  • Transfection


  • Amyloid beta-Protein Precursor
  • Dipeptides
  • Hydroxamic Acids
  • N-((2-(hydroxyaminocarbonyl)methyl)-4-methylpentanoyl)-3-(2'-naphthyl)alanylalanine, 2-aminoethylamide
  • Protease Inhibitors
  • Receptor, Muscarinic M3
  • Receptors, Muscarinic
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • ADAM Proteins
  • Metalloendopeptidases
  • ADAM17 Protein
  • ADAM17 protein, human