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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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Kinetic properties of cathepsin D and BACE 1 indicate the need to search for additional β-secretase candidate(s)

Israel Schechter1 / Etty Ziv2

1Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel

2Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel

Corresponding author

Citation Information: Biological Chemistry. Volume 389, Issue 3, Pages 313–320, ISSN (Online) 14374315, ISSN (Print) 14316730, DOI: 10.1515/BC.2008.025, March 2008

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Many studies suggest that BACE 1 is the genuine β-secretase; however, this is not undisputed. The wild-type (WT) β-site of the amyloid precursor protein (APP) present in the worldwide population is cleaved very slowly (k cat/K m: approx. 50 m -1 s-1), while proteases acting on relevant substrates are much more efficient (k cat/K m: 104–106 m -1 s-1). Knock-out of BACE 1 in mouse markedly reduces Aβ formation. Nevertheless, studies in other systems show that knock-out experiments in rodents and corresponding genetic defects in human may reveal different phenotypes. Considering these issues, we searched for other β-secretase candidate(s), identified cathepsin D, and evaluated properties of cathepsin D related to BACE 1 that were not examined previously. The kinetic constants (k cat, K m, k cat/K m) for cleaving peptides with β-sites of the WT or the mutated Swedish families (SW) APP by human BACE 1 and cathepsin D were determined and found to be similar. Western blots reveal that in human brain cathepsin D is approximately 280-fold more abundant than BACE 1. Furthermore, pepstatin A strongly inhibits the cleavage of SW and WT peptides by both brain extracts and cathepsin D, but not by BACE 1. These findings indicate that β-secretase activity observed in brain extracts is mainly due to cathepsin D. Nevertheless, as both BACE 1 and cathepsin D show poor activity towards the WT β-site sequence, it is necessary to continue the search for additional β-secretase candidate(s).

Keywords: Alzheimer's disease; amyloid precursor protein; brain abundance of BACE 1; brain abundance of cathepsin D; cleavage of β-site; kcat; Km

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