JBC

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Durkin, J. T.
Right arrow Articles by Siman, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Durkin, J. T.
Right arrow Articles by Siman, R.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

J Biol Chem, Vol. 274, Issue 29, 20499-20504, July 16, 1999

Rank-Order of Potencies for Inhibition of the Secretion of Abeta 40 and Abeta 42 Suggests That Both Are Generated by a Single gamma -Secretase

John T. Durkin, Seetha Murthy, E. Jean Husten, Stephen P. Trusko, Mary J. Savage, David P. Rotella, Barry D. Greenberg, and Robert Siman

From Cephalon, Inc., West Chester, Pennsylvania 19380

The Alzheimer's disease amyloid peptide Abeta has a heterogeneous COOH terminus, as variants 40 and 42 residues long are found in neuritic plaques and are secreted constitutively by cultured cells. The proteolytic activity that liberates the Abeta COOH terminus from the beta -amyloid precursor protein is called gamma -secretase. It could be one protease with dual specificity or two distinct enzymes. By using enzyme-linked immunosorbent assays selective for Abeta 40 or Abeta 42, we have measured Abeta secretion by a HeLa cell line, and we have examined the dose responses for a panel of five structurally diverse gamma -secretase inhibitors. The inhibitors lowered Abeta and p3 secretion and increased levels of the COOH-terminal 99-residue beta -amyloid precursor protein derivative that is the precursor for Abeta but did not alter secretion of beta -amyloid precursor protein derivatives generated by other secretases, indicating that the inhibitors blocked the gamma -secretase processing step. The dose-dependent inhibition of Abeta 42 was unusual, as the compounds elevated Abeta 42 secretion at sub-inhibitory doses and then inhibited secretion at higher doses. A compound was identified that elevated Abeta 42 secretion at a low concentration without inhibiting Abeta 42 or Abeta 40 at high concentrations, demonstrating that these phenomena are separable pharmacologically. Using either of two methods, IC50 values for inhibition of Abeta 42 and Abeta 40 were found to have the same rank-order and fall on a trend line with near-unit slope. These results favor the hypothesis that Abeta variants ending at residue 40 or 42 are generated by a single gamma -secretase.

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 Proc. Natl. Acad. Sci. USAHome page
J. Shen and R. J. Kelleher III
The presenilin hypothesis of Alzheimer's disease: Evidence for a loss-of-function pathogenic mechanism
PNAS, January 9, 2007; 104(2): 403 - 409.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
E. Rockenstein, M. Mante, M. Alford, A. Adame, L. Crews, M. Hashimoto, L. Esposito, L. Mucke, and E. Masliah
High {beta}-Secretase Activity Elicits Neurodegeneration in Transgenic Mice Despite Reductions in Amyloid-{beta} Levels: IMPLICATIONS FOR THE TREATMENT OF ALZHEIMER DISEASE
J. Biol. Chem., September 23, 2005; 280(38): 32957 - 32967.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. Weggen, J. L. Eriksen, S. A. Sagi, C. U. Pietrzik, V. Ozols, A. Fauq, Todd. E. Golde, and E. H. Koo
Evidence That Nonsteroidal Anti-inflammatory Drugs Decrease Amyloid {beta}42 Production by Direct Modulation of {gamma}-Secretase Activity
J. Biol. Chem., August 22, 2003; 278(34): 31831 - 31837.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Y. Takahashi, I. Hayashi, Y. Tominari, K. Rikimaru, Y. Morohashi, T. Kan, H. Natsugari, T. Fukuyama, T. Tomita, and T. Iwatsubo
Sulindac Sulfide Is a Noncompetitive gamma -Secretase Inhibitor That Preferentially Reduces Abeta 42 Generation
J. Biol. Chem., May 9, 2003; 278(20): 18664 - 18670.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
T. Ikeuchi, G. Dolios, S.-H. Kim, R. Wang, and S. S. Sisodia
Familial Alzheimer Disease-linked Presenilin 1 Variants Enhance Production of Both Abeta 1-40 and Abeta 1-42 Peptides That Are Only Partially Sensitive to a Potent Aspartyl Protease Transition State Inhibitor of "gamma -Secretase"
J. Biol. Chem., February 21, 2003; 278(9): 7010 - 7018.
[Abstract] [Full Text] [PDF]

Home page
 Biophys. JHome page
M. Gralle, M. M. Botelho, C. L. P. de Oliveira, I. Torriani, and S. T. Ferreira
Solution Studies and Structural Model of the Extracellular Domain of the Human Amyloid Precursor Protein
Biophys. J., December 1, 2002; 83(6): 3513 - 3524.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
R. Siman, A. G. Reaume, M. J. Savage, S. Trusko, Y.-G. Lin, R. W. Scott, and D. G. Flood
Presenilin-1 P264L Knock-In Mutation: Differential Effects on Abeta Production, Amyloid Deposition, and Neuronal Vulnerability
J. Neurosci., December 1, 2000; 20(23): 8717 - 8726.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
W. A. Maltese, S. Wilson, Y. Tan, S. Suomensaari, S. Sinha, R. Barbour, and L. McConlogue
Retention of the Alzheimer's Amyloid Precursor Fragment C99 in the Endoplasmic Reticulum Prevents Formation of Amyloid beta -Peptide
J. Biol. Chem., June 1, 2001; 276(23): 20267 - 20279.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 All ASBMB Journals   Molecular and Cellular Proteomics 
 Journal of Lipid Research   ASBMB Today 
Copyright © 1999 by the American Society for Biochemistry and Molecular Biology.