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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
Author(s) -
Marambaud Philippe,
LopezPerez Elvira,
Wilk Sherwin,
Checler Frédéric
Publication year - 1997
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1997.69062500.x
Subject(s) - lactacystin , protein kinase c , amyloid precursor protein , secretion , microbiology and biotechnology , proteasome , biology , amyloid precursor protein secretase , long term potentiation , protein kinase a , alpha secretase , p3 peptide , intracellular , kinase , proteasome inhibitor , alzheimer's disease , biochemistry , medicine , receptor , disease
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.