Caspases-2 and -8 are involved in the presenilin1/gamma-secretase-dependent cleavage of amyloid precursor protein after the induction of apoptosis.
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.
Division of Brain Diseases, Center for Biomedical Sciences, National Institute of Health, Seoul, Korea.
San Sook
SS
Chae
Chul Bae
CB
Yoo
Chulman
C
Jo
Sang-Moon
SM
Yun
Sangmee Ahn
SA
Jo
Young Ho
YH
Koh
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053143:Caspase 2 / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009154:Mutation; D009842:Oligopeptides / Q000494:pharmacology; D053764:Presenilin-1 / Q000378:metabolism*; D058255:Protease Nexins; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D019311:Staurosporine / Q000633:toxicity; D014162:Transfection
C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D000873:Anthracenes; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D009842:Oligopeptides; C508853:PSEN1 protein, human; D053764:Presenilin-1; D058255:Protease Nexins; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; C427308:benzoylcarbonyl-valyl-aspartyl-valyl-alanyl-aspartyl-fluoromethyl ketone; C403753:benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D053829:Amyloid Precursor Protein Secretases; C490360:CASP2 protein, human; C505530:CASP8 protein, human; D053143:Caspase 2; D053181:Caspase 8; D020169:Caspases; D003546:Cysteine Endopeptidases; D019311:Staurosporine