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Science 22 October 1999:
Vol. 286. no. 5440, pp. 735 - 741
DOI: 10.1126/science.286.5440.735
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Research Articles

beta -Secretase Cleavage of Alzheimer's Amyloid Precursor Protein by the Transmembrane Aspartic Protease BACE

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 1dagger

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.

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.

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

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{beta}-Site Amyloid Precursor Protein Cleaving Enzyme 1 Levels Become Elevated in Neurons around Amyloid Plaques: Implications for Alzheimer's Disease Pathogenesis.
J. Zhao, Y. Fu, M. Yasvoina, P. Shao, B. Hitt, T. O'Connor, S. Logan, E. Maus, M. Citron, R. Berry, et al. (2007)
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Inhibition of Familial Cerebral Amyloid Angiopathy Mutant Amyloid beta-Protein Fibril Assembly by Myelin Basic Protein.
M. D. Hoos, M. Ahmed, S. O. Smith, and W. E. Van Nostrand (2007)
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Presenilin/{gamma}-Secretase-mediated Cleavage Regulates Association of Leukocyte-Common Antigen-related (LAR) Receptor Tyrosine Phosphatase with beta-Catenin.
A. Haapasalo, D. Y. Kim, B. W. Carey, M. K. Turunen, W. H. Pettingell, and D. M. Kovacs (2007)
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Dominance of Amyloid Precursor Protein Sequence over Host Cell Secretases in Determining beta-Amyloid Profiles Studies of Interspecies Variation and Drug Action by Internally Standardized Immunoprecipitation/Mass Spectrometry.
P. Du, K. M. Wood, M. H. Rosner, D. Cunningham, B. Tate, and K. F. Geoghegan (2007)
J. Pharmacol. Exp. Ther. 320, 1144-1152
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RNA Interference Silencing of the Adaptor Molecules ShcC and Fe65 Differentially Affect Amyloid Precursor Protein Processing and Abeta Generation.
Z. Xie, Y. Dong, U. Maeda, W. Xia, and R. E. Tanzi (2007)
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Synapse-Associated Protein-97 Mediates {alpha}-Secretase ADAM10 Trafficking and Promotes Its Activity.
E. Marcello, F. Gardoni, D. Mauceri, S. Romorini, A. Jeromin, R. Epis, B. Borroni, F. Cattabeni, C. Sala, A. Padovani, et al. (2007)
J. Neurosci. 27, 1682-1691
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The Genetics of Alzheimer's Disease.
C. K. Chai (2007)
American Journal of Alzheimer's Disease and Other Dementias 22, 37-41
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Interferon-{gamma} and Tumor Necrosis Factor-{alpha} Regulate Amyloid-{beta} Plaque Deposition and {beta}-Secretase Expression in Swedish Mutant APP Transgenic Mice.
M. Yamamoto, T. Kiyota, M. Horiba, J. L. Buescher, S. M. Walsh, H. E. Gendelman, and T. Ikezu (2007)
Am. J. Pathol. 170, 680-692
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PAT1a Modulates Intracellular Transport and Processing of Amyloid Precursor Protein (APP), APLP1, and APLP2.
Y.-H. Kuan, T. Gruebl, P. Soba, S. Eggert, I. Nesic, S. Back, J. Kirsch, K. Beyreuther, and S. Kins (2006)
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Subcutaneous Nogo Receptor Removes Brain Amyloid-{beta} and Improves Spatial Memory in Alzheimer's Transgenic Mice.
J. H. Park, G. A. Widi, D. A. Gimbel, N. Y. Harel, D. H. S. Lee, and S. M. Strittmatter (2006)
J. Neurosci. 26, 13279-13286
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Enhanced Amyloidogenic Metabolism of the Amyloid beta-Protein Precursor in the X11L-deficient Mouse Brain.
Y. Sano, A. Syuzo-Takabatake, T. Nakaya, Y. Saito, S. Tomita, S. Itohara, and T. Suzuki (2006)
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GGA1 Is Expressed in the Human Brain and Affects the Generation of Amyloid {beta}-Peptide.
T. Wahle, D. R. Thal, M. Sastre, A. Rentmeister, N. Bogdanovic, M. Famulok, M. T. Heneka, and J. Walter (2006)
J. Neurosci. 26, 12838-12846
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LRRTM3 promotes processing of amyloid-precursor protein by BACE1 and is a positional candidate gene for late-onset Alzheimer's disease.
J. Majercak, W. J. Ray, A. Espeseth, A. Simon, X.-P. Shi, C. Wolffe, K. Getty, S. Marine, E. Stec, M. Ferrer, et al. (2006)
PNAS 103, 17967-17972
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A Century of Alzheimer's Disease.
M. Goedert and M. G. Spillantini (2006)
Science 314, 777-781
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Therapeutic approaches to Alzheimer's disease.
H.-W. Klafki, M. Staufenbiel, J. Kornhuber, and J. Wiltfang (2006)
Brain 129, 2840-2855
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Control of Peripheral Nerve Myelination by the {beta}-Secretase BACE1.
M. Willem, A. N. Garratt, B. Novak, M. Citron, S. Kaufmann, A. Rittger, B. DeStrooper, P. Saftig, C. Birchmeier, and C. Haass (2006)
Science 314, 664-666
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Intra- or Intercomplex Binding to the {gamma}-Secretase Enzyme: A MODEL TO DIFFERENTIATE INHIBITOR CLASSES.
E. E. Clarke, I. Churcher, S. Ellis, J. D. J. Wrigley, H. D. Lewis, T. Harrison, M. S. Shearman, and D. Beher (2006)
J. Biol. Chem. 281, 31279-31289
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GGA1 Acts as a Spatial Switch Altering Amyloid Precursor Protein Trafficking and Processing.
C. A. F. von Arnim, R. Spoelgen, I. D. Peltan, M. Deng, S. Courchesne, M. Koker, T. Matsui, H. Kowa, S. F. Lichtenthaler, M. C. Irizarry, et al. (2006)
J. Neurosci. 26, 9913-9922
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Neuritic Deposits of Amyloid-{beta} Peptide in a Subpopulation of Central Nervous System-Derived Neuronal Cells..
Z. Muresan and V. Muresan (2006)
Mol. Cell. Biol. 26, 4982-4997
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Increased BACE1 maturation contributes to the pathogenesis of Alzheimer's disease in Down syndrome.
X. Sun, Y. Tong, H. Qing, C.-H. Chen, and W. Song (2006)
FASEB J 20, 1361-1368
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BACE2, as a novel APP {theta}-secretase, is not responsible for the pathogenesis of Alzheimer's disease in Down syndrome.
X. Sun, G. He, and W. Song (2006)
FASEB J 20, 1369-1376
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Targeting the Role of the Endosome in the Pathophysiology of Alzheimer's Disease: A Strategy for Treatment.
B. A. Tate and P. M. Mathews (2006)
Sci. Aging Knowl. Environ. 2006, re2
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Trafficking of Alzheimer's Disease-Related Membrane Proteins and Its Participation in Disease Pathogenesis.
T. Suzuki, Y. Araki, T. Yamamoto, and T. Nakaya (2006)
J. Biochem. 139, 949-955
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Presenilin/{gamma}-secretase activity regulates protein clearance from the endocytic recycling compartment.
M. Zhang, A. Haapasalo, D. Y. Kim, L. A. M. Ingano, W. H. Pettingell, and D. M. Kovacs (2006)
FASEB J 20, 1176-1178
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