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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred

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Volume 386, Issue 9 (Sep 2005)

Issues

Inhibition of cathepsin B reduces β-amyloid production in regulated secretory vesicles of neuronal chromaffin cells: evidence for cathepsin B as a candidate β-secretase of Alzheimer's disease

Vivian Hook
  • Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093, USA
  • Other articles by this author:
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/ Thomas Toneff
  • Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093, USA
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/ Matthew Bogyo / Doron Greenbaum
  • Department of Pharmaceutical Chemistry, School of Pharmacy, University of California at San Francisco, San Francisco, CA 94143, USA
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/ Katalin F. Medzihradszky
  • Department of Pharmaceutical Chemistry, School of Pharmacy, University of California at San Francisco, San Francisco, CA 94143, USA
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/ John Neveu / William Lane / Gregory Hook / Terry Reisine
Published Online: 2005-09-09 | DOI: https://doi.org/10.1515/BC.2005.108

Abstract

The regulated secretory pathway of neurons is the major source of extracellular Aβ that accumulates in Alzheimer's disease (AD). Extracellular Aβ secreted from that pathway is generated by β-secretase processing of amyloid precursor protein (APP). Previously, cysteine protease activity was demonstrated as the major β-secretase activity in regulated secretory vesicles of neuronal chromaffin cells. In this study, the representative cysteine protease activity in these secretory vesicles was purified and identified as cathepsin B by peptide sequencing. Immunoelectron microscopy demonstrated colocalization of cathepsin B with Aβ in these vesicles. The selective cathepsin B inhibitor, CA074, blocked the conversion of endogenous APP to Aβ in isolated regulated secretory vesicles. In chromaffin cells, CA074Me (a cell permeable form of CA074) reduced by about 50% the extracellular Aβ released by the regulated secretory pathway, but CA074Me had no effect on Aβ released by the constitutive pathway. Furthermore, CA074Me inhibited processing of APP into the COOH-terminal β-secretase-like cleavage product. These results provide evidence for cathepsin B as a candidate β-secretase in regulated secretory vesicles of neuronal chromaffin cells. These findings implicate cathepsin B as β-secretase in the regulated secretory pathway of brain neurons, suggesting that inhibitors of cathepsin B may be considered as therapeutic agents to reduce Aβ in AD.

Keywords: Alzheimer's disease; β-amyloid; β-secretase; cathepsin B; cysteine protease; regulated secretory pathway

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About the article

Corresponding author


Received: 2005-01-07

Accepted: 2005-06-30

Published Online: 2005-09-09

Published in Print: 2005-09-01


Citation Information: Biological Chemistry, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/BC.2005.108.

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