Constitutive and protein kinase C-regulated secretory cleavage of Alzheimer's β-amyloid precursor protein: Different control of early and late events by the proteasome

The physiological processing of the β-amyloid precursor protein (βAPP) by a protease called α-secretase gives rise to APPα, a C-terminally truncated fragment of βAPP 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 APPα 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 APPα 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 APPα recovery, whereas long-term treatment of the cells (15-20 h) with the blocking agents leads to an overall decrease in the secretion of APPα. Such a dual effect was not observed on constitutive APPα secretion and intracellular formation generated by HK293 cells, which both only increase upon inhibitor treatments. Similar effects on the constitutive and PKC- regulated APPα secretion were observed with PC12 cells. Altogether, these data suggest distinct mechanisms underlying basal and PKC-regulated APPα production, indicating that this multicatalytic complex appears as a key contributor of the α-secretase pathway.