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Role of protein kinase Cα in the regulated secretion of the amyloid precursor protein

Molecular Psychiatry volume 8, pages 209–216 (2003)Cite this article

Abstract

Protein 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 (sAPPα) and reduce the secretion of β-amyloid peptides. Experimental evidence suggests that specific isoforms of PKC, such as PKCα and PKCɛ, are involved in the regulation of APP metabolism. In this study, we characterized the role of PKCα in the regulated secretion of APP using wild-type SH-SY5Y neuroblastoma cells and cells transfected with a plasmid expressing PKCα antisense cDNA. Cells expressing antisense PKCα secrete less sAPPα in response to phorbol esters. In contrast, carbachol increases the secretion of sAPPα to similar levels in wild-type cells and in cells transfected with antisense PKCα 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 PKCα 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.

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Acknowledgements

We are grateful to Dr Thomas B Shea for the gift of SH-SY5Y cells transfected with antisense PKCα (SYα4) and the parental non-transfected SH-SY5Y cell line (SYwt). We are also grateful to Prof. Mark O Lively of Wake Forest University School of Medicine, Winston Salem, NC, USA for helpful discussions and a careful proofreading of the manuscript. The financial support of TELETHON—Italy, Grant # E.0866 to SG is gratefully acknowledged. This research was also funded by MIUR—Cofin 2000 (SG) and Ministero Sanità—Progetto Alzheimer (MR).

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  1. Department of Experimental and Applied Pharmacology, University of Pavia, Italy

    M Racchi, M Mazzucchelli, A Pascale, M Sironi & S Govoni

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  1. M Racchi
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Correspondence to S Govoni.

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Racchi, M., Mazzucchelli, M., Pascale, A. et al. Role of protein kinase Cα in the regulated secretion of the amyloid precursor protein. Mol Psychiatry 8, 209–216 (2003). https://doi.org/10.1038/sj.mp.4001204

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