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Originally published In Press as doi:10.1074/jbc.M211485200 on December 5, 2002

J. Biol. Chem., Vol. 278, Issue 8, 5531-5538, February 21, 2003
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Identification of a beta -Secretase Activity, Which Truncates Amyloid beta -Peptide after Its Presenilin-dependent Generation*

Regina Fluhrerab, Gerd Multhaupbcd, Andrea Schlicksuppc, Masayasu Okochie, Masatoshi Takedae, Sven Lammicha, Michael Willema, Gil Westmeyera, Wolfram Bodef, Jochen Walteraghi, and Christian Haassahj

From the a Adolf-Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Schillerstrasse 44, Ludwig-Maximilians University, 80336 Munich, Germany, the c ZMBH-Center for Molecular Biology, University of Heidelberg, Im Neuenheimer Feld 282, Germany, the e Department of Postgenomics and Diseases, Division of Psychiatry and Behavioral Proteomics, Osaka University Graduate School of Medicine, 565-0871 Osaka, Japan, and the f Max-Planck Institute for Biochemistry, Am Klopferspitz 18a, 82152 Martinsried, Germany

The beta -amyloid precursor protein (beta APP) is proteolytically processed by two secretase activities to produce the pathogenic amyloid beta -peptide (Abeta ). N-terminal cleavage is mediated by beta -secretase (BACE) whereas C-terminal intramembraneous cleavage is exerted by the presenilin (PS) gamma -secretase complex. The Abeta -generating gamma -secretase cleavage principally occurs after amino acid 40 or 42 and results in secretion of Abeta -(1-40) or Abeta -(1-42). Upon overexpression of BACE in cultured cells we unexpectedly noticed a reduction of secreted Abeta -(1-40/42). However, mass spectrometry revealed a truncated Abeta species, which terminates at amino acid 34 (Abeta -(1-34)) suggesting an alternative gamma -secretase cut. Indeed, expression of a loss-of-function variant of PS1 inhibited not only the production of Abeta -(1-40) and Abeta -(1-42) but also that of Abeta -(1-34). However, expression levels of BACE correlate with the amount of Abeta -(1-34), and Abeta -(1-34) is produced at the expense of Abeta -(1-40) and Abeta -(1-42). Since this suggested that BACE is involved in a C-terminal truncation of Abeta , we incubated purified BACE with Abeta -(1-40) in vitro. Under these conditions Abeta -(1-34) was generated. Moreover, when conditioned media containing Abeta -(1-40) and Abeta -(1-42) were incubated with cells expressing a loss-of-function PS1 variant together with BACE, Abeta -(1-34) was efficiently produced in vivo. These data demonstrate that an apparently gamma -secretase-dependent Abeta derivative is produced after the generation of the non-truncated Abeta via an additional and unexpected activity of BACE.

* This work was supported by the Deutsche Forschungsgemeinschaft (SFB 596-Project B1 (to C. H.) and the Priority Program (to J. W., C. H., and G. M.)) and the DIADEM Project (to C. H.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

b These authors contributed equally to this work.

d Present address: Dept. of Chemistry/Biochemistry, Freie Universität Berlin, Thielallee 63, 14195 Berlin, Germany.

g Present address: Dept. of Neurology, University of Bonn; Sigmund-Freud-Str. 25, 53105 Bonn, Germany.

h These authors contributed equally to this work.

i To whom correspondence may be addressed. Tel.: 49-89-5996-471/472; Fax: 49-89-5996-415; E-mail: chaass@pbm.med.uni-muenchen.de.

j To whom correspondence may be addressed. Tel.: 49-228-2879782; Fax: 49-228-2874387; E-mail: jochen.walter@ukb.uni-bonn.de.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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