β-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE

Robert Vassar, Brian D. Bennett, Safura Babu-Khan, Steve Kahn, Elizabeth A. Mendiaz, Paul Denis, David B. Teplow, Sandra Ross, Patricia Amarante, Richard Loeloff, Yi Luo, Seth Fisher, Janis Fuller, Steven Edenson, Jackson Lile, Mark A. Jarosinski, Anja Leona Biere, Eileen Curran, Teresa Burgess, Jean Claude LouisFrank Collins, James Treanor, Gary Rogers, Martin Citron*

*Corresponding author for this work

Research output: Contribution to journalArticle

2994 Scopus citations

Abstract

Cerebral deposition of amyloid β peptide (Aβ) is an early and critical feature of Alzheimer's disease. Aβ generation depends on proteolytic cleavage of the amyloid precursor protein (APP) by two unknown proteases: β- secretase and γ-secretase. These proteases are prime therapeutic targets. A transmembrane aspartic protease with all the known characteristics of β- secretase was cloned and characterized. Overexpression of this protease, termed BACE (for beta-site APP-cleaving enzyme) increased the amount of β- secretase cleavage products, and these were cleaved exactly and only at known β-secretase positions. Antisense inhibition of endogenous BACE messenger RHA decreased the amount of β-secretase cleavage products, and purified BACE protein cleaved APP-derived substrates with the same sequence specificity as β-secretase. Finally, the expression pattern and subcellular localization of BACE were consistent with that expected for β-secretase. Future development of BACE inhibitors may prove beneficial for the treatment of Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)735-741
Number of pages7
JournalScience
Volume286
Issue number5440
DOIs
StatePublished - Oct 22 1999

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'β-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE'. Together they form a unique fingerprint.

  • Cite this

    Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., Teplow, D. B., Ross, S., Amarante, P., Loeloff, R., Luo, Y., Fisher, S., Fuller, J., Edenson, S., Lile, J., Jarosinski, M. A., Biere, A. L., Curran, E., Burgess, T., ... 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