Robert Vassar, ^1* Brian D. Bennett, ^1* Safura Babu-Khan, ¹ Steve Kahn, ¹ Elizabeth A. Mendiaz, ¹ Paul Denis, ¹ David B. Teplow, ² Sandra Ross, ¹ Patricia Amarante, ¹ Richard Loeloff, ¹ Yi Luo, ¹ Seth Fisher, ¹ Janis Fuller, ¹ Steven Edenson, ¹ Jackson Lile, ¹ Mark A. Jarosinski, ¹ Anja Leona Biere, ¹ Eileen Curran, ¹ Teresa Burgess, ¹ Jean-Claude Louis, ¹ Frank Collins, ¹ James Treanor, ¹ Gary Rogers, ¹ Martin Citron ¹

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

¹ Amgen, Inc., One Amgen Center Drive, M/S 29-2-B, Thousand Oaks, CA 91320-1799, USA.
² Department of Neurology, Harvard Medical School, and Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, 02115, USA.
^*   These authors contributed equally to this work.

   To whom correspondence should be addressed. E-mail: mcitron{at}amgen.com