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Science 24 August 2001:
Vol. 293. no. 5534, pp. 1449 - 1454
DOI: 10.1126/science.1064638
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Review

A Portrait of Alzheimer Secretases--New Features and Familiar Faces

William P. Esler, Michael S. Wolfe*

The amyloid beta -peptide (Abeta ) is a principal component of the cerebral plaques found in the brains of patients with Alzeheimer's disease (AD). This insoluble 40- to 42-amino acid peptide is formed by the cleavage of the Abeta precursor protein (APP). The three proteases that cleave APP, alpha -, beta -, and gamma -secretases, have been implicated in the etiology of AD. beta -Secretase is a membrane-anchored protein with clear homology to soluble aspartyl proteases, and alpha -secretase displays characteristics of certain membrane-tethered metalloproteases. gamma -Secretase is apparently an oligomeric complex that includes the presenilins, which may be the catalytic component of this protease. Identification of the alpha -, beta -, and gamma -secretases provides potential targets for designing new drugs to treat AD.

Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
*   To whom correspondence should be addressed. E-mail: mwolfe{at}rics.bwh.harvard.edu

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J. Biol. Chem. 278, 13077-13085
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{gamma}-Secretase--Intramembrane Protease with a Complex.
M. S. Wolfe (2003)
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Tumor Necrosis Factor-alpha Converting Enzyme/ADAM 17 Mediates MUC1 Shedding.
A. Thathiah, C. P. Blobel, and D. D. Carson (2003)
J. Biol. Chem. 278, 3386-3394
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Capacitive Calcium Entry Is Directly Attenuated by Mutant Presenilin-1, Independent of the Expression of the Amyloid Precursor Protein.
J. Herms, I. Schneider, I. Dewachter, N. Caluwaerts, H. Kretzschmar, and F. Van Leuven (2003)
J. Biol. Chem. 278, 2484-2489
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Amyloidogenic processing of the Alzheimer {beta}-amyloid precursor protein depends on lipid rafts.
R. Ehehalt, P. Keller, C. Haass, C. Thiele, and K. Simons (2003)
J. Cell Biol. 160, 113-123
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Presenilin-dependent Intramembrane Proteolysis of CD44 Leads to the Liberation of Its Intracellular Domain and the Secretion of an Abeta -like Peptide.
S. Lammich, M. Okochi, M. Takeda, C. Kaether, A. Capell, A.-K. Zimmer, D. Edbauer, J. Walter, H. Steiner, and C. Haass (2002)
J. Biol. Chem. 277, 44754-44759
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The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for {alpha}-secretase activity in fibroblasts.
D. Hartmann, B. de Strooper, L. Serneels, K. Craessaerts, A. Herreman, W. Annaert, L. Umans, T. Lubke, A. Lena Illert, K. von Figura, et al. (2002)
Hum. Mol. Genet. 11, 2615-2624
   Abstract »    Full Text »    PDF »
Stimulation of Enveloped Virus Infection by beta -Amyloid Fibrils.
W. M. Wojtowicz, M. Farzan, J. L. Joyal, K. Carter, G. J. Babcock, D. I. Israel, J. Sodroski, and T. Mirzabekov (2002)
J. Biol. Chem. 277, 35019-35024
   Abstract »    Full Text »    PDF »
Complex N-linked Glycosylated Nicastrin Associates with Active gamma -Secretase and Undergoes Tight Cellular Regulation.
W. T. Kimberly, M. J. LaVoie, B. L. Ostaszewski, W. Ye, M. S. Wolfe, and D. J. Selkoe (2002)
J. Biol. Chem. 277, 35113-35117
   Abstract »    Full Text »    PDF »
Non-steroidal Anti-inflammatory Drugs Stimulate Secretion of Non-amyloidogenic Precursor Protein.
Y. Avramovich, T. Amit, and M. B. H. Youdim (2002)
J. Biol. Chem. 277, 31466-31473
   Abstract »    Full Text »    PDF »
Presenilin-1 affects trafficking and processing of {beta}APP and is targeted in a complex with nicastrin to the plasma membrane.
C. Kaether, S. Lammich, D. Edbauer, M. Ertl, J. Rietdorf, A. Capell, H. Steiner, and C. Haass (2002)
J. Cell Biol. 158, 551-561
   Abstract »    Full Text »    PDF »
Intracellular Activation of Human Adamalysin 19/Disintegrin and Metalloproteinase 19 by Furin Occurs via One of the Two Consecutive Recognition Sites.
T. Kang, Y.-G. Zhao, D. Pei, J. F. Sucic, and Q.-X. A. Sang (2002)
J. Biol. Chem. 277, 25583-25591
   Abstract »    Full Text »    PDF »
Proteolytic Processing of Low Density Lipoprotein Receptor-related Protein Mediates Regulated Release of Its Intracellular Domain.
P. May, Y. K. Reddy, and J. Herz (2002)
J. Biol. Chem. 277, 18736-18743
   Abstract »    Full Text »    PDF »
The gamma -secretase-generated intracellular domain of beta -amyloid precursor protein binds Numb and inhibits Notch signaling.
R. Roncarati, N. Sestan, M. H. Scheinfeld, B. E. Berechid, P. A. Lopez, O. Meucci, J. C. McGlade, P. Rakic, and L. D'Adamio (2002)
PNAS 99, 7102-7107
   Abstract »    Full Text »    PDF »
Tyrosine Phosphorylation of the beta -Amyloid Precursor Protein Cytoplasmic Tail Promotes Interaction with Shc.
P. E. Tarr, R. Roncarati, G. Pelicci, P. G. Pelicci, and L. D'Adamio (2002)
J. Biol. Chem. 277, 16798-16804
   Abstract »    Full Text »    PDF »
Neuronal Deficiency of Presenilin 1 Inhibits Amyloid Plaque Formation and Corrects Hippocampal Long-Term Potentiation But Not a Cognitive Defect of Amyloid Precursor Protein [V717I] Transgenic Mice.
I. Dewachter, D. Reverse, N. Caluwaerts, L. Ris, C. Kuiperi, C. Van den Haute, K. Spittaels, L. Umans, L. Serneels, E. Thiry, et al. (2002)
J. Neurosci. 22, 3445-3453
   Abstract »    Full Text »    PDF »
Insulin-degrading Enzyme Rapidly Removes the beta -Amyloid Precursor Protein Intracellular Domain (AICD).
D. Edbauer, M. Willem, S. Lammich, H. Steiner, and C. Haass (2002)
J. Biol. Chem. 277, 13389-13393
   Abstract »    Full Text »    PDF »
Presenilin-dependent gamma -Secretase-like Intramembrane Cleavage of ErbB4.
H.-J. Lee, K.-M. Jung, Y. Z. Huang, L. B. Bennett, J. S. Lee, L. Mei, and T.-W. Kim (2002)
J. Biol. Chem. 277, 6318-6323
   Abstract »    Full Text »    PDF »


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Science. ISSN 0036-8075 (print), 1095-9203 (online)