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Molecular Psychiatry (2003) 8, 209216
& 2003 Nature Publishing Group All rights reserved 1359-4184/03 $25.00www.nature.com/mpORIGINAL RESEARCH ARTICLERole of protein kinase Ca in the regulated secretion of the
amyloid precursor proteinM Racchi, M Mazzucchelli, A Pascale, M Sironi and S GovoniDepartment of Experimental and Applied Pharmacology, University of Pavia, ItalyKeywords: amyloid precursor protein; signal transduction; protein kinase C; neuroblastoma cells; phorbol ester;
cholinergicProtein kinase C (PKC) has a key role in the signal
transduction machinery involved in the regulation of
amyloid precursor protein (APP) metabolism. Direct and
indirect receptor-mediated activation of PKC has been
shown to increase the release of soluble APP (sAPPa)
and reduce the secretion of b-amyloid peptides. Experimental evidence suggests that specific isoforms of PKC,
such as PKCa and PKCe, are involved in the regulation
of APP metabolism. In this study, we characterized the
role of PKCa in the regulated secretion of APP using
wild-type SH-SY5Y neuroblastoma cells and cells transfected with a plasmid expressing PKCa antisense cDNA.
Cells expressing antisense PKCa secrete less sAPPa in
response to phorbol esters. In contrast, carbachol
increases the secretion of sAPPa to similar levels in
wild-type cells and in cells transfected with antisense
PKCa by acting on APP metabolism through an indirect
pathway partially involving the activation of PKC. These
results suggest that the direct PKC-dependent activation of the APP secretory pathway is compromised by
reduced PKCa expression and a specific role of this
isoform in these mechanisms. On the other hand,
indirect pathways that are also partially dependent on
the mitogen-activated protein kinase signal transduction mechanism remain unaffected and constitute a
redundant, compensatory mechanism within the APP
secretory pathway.Molecular Psychiatry (2003) 8, 209216. doi:10.1038/
sj.mp.4001204IntroductionThe metabolic fate of the amyloid precursor protein
(APP) is one of the key factors in the pathogenesis
of Alzheimers disease (AD).1 The routes of APP
metabolism result in different pathways, leading to
proteolytic processing of the precursor by at least
three proteolytic activities that have been more
closely characterized in recent years.25 At the cell
surface or in a secretory vesicle in its immediate
proximity, a protease named a secretase cleaves
APP in the extracellular domain and releases the
ectodomain (sAPPa or soluble APPa) into the extracellular space. This proteolytic cleavage constitutes
the non-amyloidogenic pathway because it occurs
within the...