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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Ludwig, Stephan / Sies, Helmut / Turk, Boris / Wittinghofer, Alfred

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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 Hook1 / Thomas Toneff2 / Matthew Bogyo3 / Doron Greenbaum4 / Katalin F. Medzihradszky5 / John Neveu6 / William Lane7 / Gregory Hook8 / Terry Reisine9

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Corresponding author

Citation Information: Biological Chemistry. Volume 386, Issue 9, Pages 931–940, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: 10.1515/BC.2005.108, September 2005

Publication History

Received:
January 7, 2005
Accepted:
June 30, 2005
Published Online:
2005-09-09

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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