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 Louis, Frank Collins, James Treanor, Gary Rogers, Martin Citron- Multidisciplinary
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 RNA 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.