Caspases-2 and -8 are involved in the presenilin1/gamma-secretase-dependent cleavage of amyloid precursor protein after the induction of apoptosis

J Neurosci Res. 2010 Jul;88(9):1926-33. doi: 10.1002/jnr.22356.

Abstract

The presenilin/gamma-secretase protease cleaves many type-I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP). Previous studies have shown that apoptosis induces alterations in Abeta production in a caspase-dependent manner. Here, we report that staurosporine (STS)-induced apoptosis induces caspase-8 and/or-2-dependent gamma-secretase activation. Blocking of caspase activity with caspase-8 inhibitor z-IETD-fmk, and caspase-2 inhibitor z-VDVAD-fmk reduced Abeta production by STS in H4 cells expressing the Swedish mutant of APP (HSW) or APP-C99 (H4-C99). There was no inhibitory effect of other caspases (-1, -3, -5, -6, -9) on Abeta production by STS. This finding was further supported by evidence that siRNA transfection, depleting caspase-2 or -8 levels, lowered Abeta production in HSW and H4-C99 cells without affecting expression of APP or gamma-secretase complex. In addition, Abeta production by STS was decreased by JNK inhibitors, SP600125. These results suggest that caspase-2 and/or -8 is involved in presenilin/gamma-secretase activation and Abeta production in apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Anthracenes / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Caspase 2 / genetics
  • Caspase 2 / metabolism*
  • Caspase 8 / genetics
  • Caspase 8 / metabolism*
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism*
  • Cysteine Proteinase Inhibitors / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / toxicity
  • Humans
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mutation
  • Oligopeptides / pharmacology
  • Presenilin-1 / metabolism*
  • Protease Nexins
  • RNA, Small Interfering
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Staurosporine / toxicity
  • Transfection

Substances

  • APP protein, human
  • Amyloid beta-Protein Precursor
  • Anthracenes
  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors
  • Enzyme Inhibitors
  • Oligopeptides
  • PSEN1 protein, human
  • Presenilin-1
  • Protease Nexins
  • RNA, Small Interfering
  • Receptors, Cell Surface
  • benzoylcarbonyl-valyl-aspartyl-valyl-alanyl-aspartyl-fluoromethyl ketone
  • benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone
  • pyrazolanthrone
  • JNK Mitogen-Activated Protein Kinases
  • Amyloid Precursor Protein Secretases
  • CASP2 protein, human
  • CASP8 protein, human
  • Caspase 2
  • Caspase 8
  • Caspases
  • Cysteine Endopeptidases
  • Staurosporine