β-Secretase Cleavage of Alzheimer's Amyloid Precursor Protein by the Transmembrane Aspartic Protease BACE
Robert J. Vassar, Brian D. Bennett, Safura Babu‐Khan, Steve Kahn, Elizabeth A. Mendiaz, Paul E. Denis, David B. Teplow, Sandra L. Ross, Patricia Amarante, Richard J. Loeloff, Yi Luo, Seth Fisher, Janis Fuller, Steven Edenson, Jackson Lile, Mark A. Jarosinski, Anja Leona Biere, Eileen J. Curran, Teresa L. Burgess, Jean-Claude Louis, James J. S. Treanor, Gary N. Rogers, Martin Citron
Science · 1999 · 3,910 citationsOpen access
Abstract
Cerebral deposition of amyloid beta peptide (Abeta) is an early and critical feature of Alzheimer's disease. Abeta generation depends on proteolytic cleavage of the amyloid precursor protein (APP) by two unknown proteases: beta-secretase and gamma-secretase. These proteases are prime therapeutic targets. A transmembrane aspartic protease with all the known characteristics of beta-secretase was cloned and characterized. Overexpression of this protease, termed BACE (for beta-site APP-cleaving enzyme) increased the amount of beta-secretase cleavage products, and these were cleaved exactly and only at known beta-secretase positions. Antisense inhibition of endogenous BACE messenger RNA decreased the amount of beta-secretase cleavage products, and purified BACE protein cleaved APP-derived substrates with the same sequence specificity as beta-secretase. Finally, the expression pattern and subcellular localization of BACE were consistent with that expected for beta-secretase. Future development of BACE inhibitors may prove beneficial for the treatment of Alzheimer's disease.
Cite this paper
Vassar, R. J., Bennett, B. D., Babu‐Khan, S., Kahn, S., Mendiaz, E. A., Denis, P. E., Teplow, D. B., Ross, S. L., Amarante, P., Loeloff, R. J., Luo, Y., Fisher, S., Fuller, J., Edenson, S., Lile, J., Jarosinski, M. A., Biere, A. L., Curran, E. J., Burgess, T. L., … Citron, M. (1999). β-Secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science, 286(5440), 735–741. https://doi.org/10.1126/science.286.5440.735
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