Constitutive and protein kinase C-regulated secretory cleavage of Alzheimer's beta-amyloid precursor protein: different control of early and late events by the proteasome.
The physiological processing of the beta-amyloid precursor protein (betaAPP) by a protease called alpha-secretase gives rise to APP alpha, a C-terminally truncated fragment of betaAPP with known neurotrophic and cytoprotective properties. Several lines of evidence indicate that protein kinase C (PKC)-mediated events regulate this physiological pathway. We show here that the proteasome multicatalytic complex modulates the phorbol 12,13-dibutyrate-stimulated APP alpha secretion at several levels in human kidney 293 (HK293) cells. Two blocking agents of the proteasome, namely, Z-IE(Ot-Bu)A-leucinal and lactacystin, elicit a dual effect on PKC-regulated APP alpha secretion by metabolically labeled HK293 cells. Thus, short periods of preincubation (2-5 h) of the cells with the inhibitors trigger a drastic potentiation of APP alpha recovery, whereas long-term treatment of the cells (15-20 h) with the blocking agents leads to an overall decrease in the secretion of APP alpha. Such a dual effect was not observed on constitutive APP alpha secretion and intracellular formation generated by HK293 cells, which both only increase upon inhibitor treatments. Similar effects on the constitutive and PKC-regulated APP alpha secretion were observed with PC12 cells. Altogether, these data suggest distinct mechanisms underlying basal and PKC-regulated APP alpha production, indicating that this multicatalytic complex appears as a key contributor of the alpha-secretase pathway.
Marambaud
P
P
Institut de Pharmacologie Moléculaire et Cellulaire, UPR 411 du CNRS, Sophia Antipolis, Valbonne, France.
Lopez-Perez
E
E
Wilk
S
S
Checler
F
F
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000502:physiology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009097:Multienzyme Complexes / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D016716:PC12 Cells / Q000378:metabolism; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats; D013997:Time Factors
D016564:Amyloid beta-Protein Precursor; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D009842:Oligopeptides; C090535:benzyloxycarbonyl-isoleucyl-glutamyl(O-tert-butyl)-alanyl-leucinal; C067713:lactacystin; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine