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Thromb Haemost 1999; 81(04): 630-637
DOI: 10.1055/s-0037-1614537
Rapid Communication
Schattauer GmbH

Thrombin Induces Surface and Intracellular Secretion of Amyloid Precursor Protein from Human Endothelial Cells

John R. Ciallella
1   From the Department of Microbiology and Immunology, KY, USA
2   Sanders Brown Research Center on Aging, KY, USA
,
Helmer Figueiredo
3   Department of Toxicology, University of Kentucky College of Medicine, Lexington, KY, USA
,
Virginia Smith-Swintosky   *
2   Sanders Brown Research Center on Aging, KY, USA
,
Joseph P. McGillis
1   From the Department of Microbiology and Immunology, KY, USA
2   Sanders Brown Research Center on Aging, KY, USA
› Author AffiliationsThis work was supported by an ADRC Pilot Project, NIH (JPM), and by an NIMH pre-doctoral fellowship 5 F31 MH10622-02 (JRC).
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Publication History

Received 23 June 1998

Accepted after revision 04 January 1999

Publication Date:
09 December 2017 (online)

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Summary

Thrombin, a major coagulant and inflammatory mediator, was shown to regulate amyloid precursor protein (APP) secretion. APP is the protein from which the amyloid beta peptide (Aß) is derived. Aß forms the core of vascular and cerebral plaques in Alzheimer’s disease (AD). In this study, human umbilical vein endothelial cells (HUVEC) were used to examine the effects of thrombin on APP expression. Cell supernatants from thrombin-treated HUVEC were immunoblotted to measure secreted APP. Thrombin-induced secretion of APP peaks at approximately 30 min post-treatment. Immunohistochemical analysis found that APP is not colocalized with or secreted through the same pathway as coagulation factor VIII. The secretion of APP is thrombin receptor-mediated, since it is inhibited by the thrombin antagonist N-Acetyl-D-Phe-Pro1Amido-4-Guanidino-Butyl-1-Boronic Acid. It also is induced by treatment with a calcium ionophore. Moreover, APP secretion is protein kinase C (PKC)-dependent because it is blocked by the PKC inhibitor bisindolylmaleimide. APP secretion also occurs from the cell surface, possibly through direct cleavage by thrombin. Immunoreactivity on the surface of HUVEC decreased after thrombin treatment but not after treatment with a non-proteolytic thrombin receptor activator. These data suggest that thrombin induces APP secretion through a PKC-dependent mechanism, as well as from the cell surface. Our results are consistent with thrombin playing a role in AD pathology.

* Present address: Robert Wood Johnson Pharmaceutical Research Institute, Spring House, PA 19477, USA


 

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