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.
Chae
San Sook
SS
Division of Brain Diseases, Center for Biomedical Sciences, National Institute of Health, Seoul, Korea.
Yoo
Chul Bae
CB
Jo
Chulman
C
Yun
Sang-Moon
SM
Jo
Sangmee Ahn
SA
Koh
Young Ho
YH
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