New protease inhibitors prevent γ-secretase-mediated production of Aβ40/42 without affecting Notch cleavage (original) (raw)

Nature Cell Biology volume 3, pages 507–511 (2001)Cite this article

Abstract

We have designed new non-peptidic potential inhibitors of γ-secretase and examined their ability to prevent production of amyloid-β 40 (Aβ40) and Aβ42 by human cells expressing wild-type and Swedish-mutant β-amyloid precursor protein (βAPP). Here we identify three such agents that markedly reduce recovery of both Aβ40 and Aβ42 produced by both cell lines, and increase that of C99 and C83, the carboxy-terminal fragments of βAPP that are derived from β-and α-secretase, respectively. Furthermore, we show that these inhibitors do not affect endoproteolysis of endogenous or overexpressed presenilins. These inhibitors are totally unable to affect the mΔEnotch-1 cleavage that leads to generation of the Notch intracellular domain (NICD). These represent the first non-peptidic inhibitors that are able to prevent γ-secretase cleavage of βAPP without affecting processing of mΔEnotch-1 or endoproteolysis of presenilins. The distinction between these two proteolytic events, which are both prevented by disruption of presenilin genes, indicates that although they are intimately linked with βAPP and Notch maturation, presenilins are probably involved in the control of maturation processes upstream of enzymes that cleave γ-secretase and Notch.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 print issues and online access

$209.00 per year

only $17.42 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

γ-Secretase in Alzheimer’s disease

Article Open access 08 April 2022

References

  1. Vassar, R. & Citron, M. Neuron 27, 419–422 (2000).
    Article CAS Google Scholar
  2. De Strooper, B et al. Nature 391, 387–390 (1998).
    Article CAS Google Scholar
  3. Herreman, A. et al. Nature Cell Biol. 2, 461–462 (2000).
    Article CAS Google Scholar
  4. Zhang, Z. et al. Nature Cell Biol. 2, 463–465 (2000).
    Article CAS Google Scholar
  5. Shen, J. et al. Cell 89, 629–639 (1997).
    Article CAS Google Scholar
  6. Davis, J. A. et al. Neuron 20, 603–609 (1998).
    Article CAS Google Scholar
  7. Donoviel, D. B. et al. Genes Dev. 13, 2801–2810 (1999).
    Article CAS Google Scholar
  8. Artavanis-Tsakonas, S., Matsuno, K. & Fortini, M. E. Science 268, 225–232 (1995).
    Article CAS Google Scholar
  9. Schroeter, E. H., Kisslinger, J. A. & Kopan, R. Nature 28, 382–386 (1998).
    Article Google Scholar
  10. De Strooper, B. et al. Nature 398, 518–522 (1999).
    Article CAS Google Scholar
  11. Checler, F. Mol. Neurobiol. 19, 255–265 (1999).
    Article CAS Google Scholar
  12. Wolfe, M. S. et al. Nature 398, 513–517 (1999).
    Article CAS Google Scholar
  13. Li, Y-M. et al. Proc. Natl Acad. Sci. USA 97, 6138–6143 (2000).
    Article CAS Google Scholar
  14. Li, Y-M. et al. Nature 405, 689–694 (2000).
    Article CAS Google Scholar
  15. Esler, W. P. et al. Nature Cell Biol. 2, 428–434 (2000).
    Article CAS Google Scholar
  16. Seiffer, D. et al. J. Biol. Chem. 275, 34086–34091 (2000).
    Article Google Scholar
  17. Christie, G. et al. J. Neurochem. 73, 195–204 (1999).
    Article CAS Google Scholar
  18. Citron, M. et al. Neuron 17, 171–179 (1996).
    Article CAS Google Scholar
  19. Nakajima, K., Powers, J. C., Ashe, B. M. & Zimmerman, M. J. Biol. Chem. 254, 4027–4032 (1979).
    CAS Google Scholar
  20. Barelli, H. et al. Mol. Med. 3, 695–707 (1997).
    Article CAS Google Scholar
  21. Ancolio, C. et al. Proc. Natl Acad. Sci. USA 96, 4119–4124 (1999).
    Article CAS Google Scholar
  22. Wolfe, M. S. J. Med. Chem. 41, 6–9 (1998).
    Article CAS Google Scholar
  23. Kopan, R., Schroeter, E. H., Weintraub, H. & Nye, J. S. Proc. Natl Acad. Sci. USA 93, 1683–1688 (1996).
    Article CAS Google Scholar
  24. Ray, W. J. J. Biol. Chem. 274, 36801–36807 (1999).
    Article CAS Google Scholar
  25. Yu, G. J. Biol. Chem. 275, 27348–27353 (2000).
    CAS Google Scholar
  26. Berezovska, O. et al. J. Neurochem. 75, 583–593 (2000).
    Article CAS Google Scholar
  27. Higaki, J., Quon, D., Zhong, Z. & Cordell, B. Neuron 14, 651–659 (1995).
    Article CAS Google Scholar
  28. Citron, M. et al. Proc. Natl Acad. Sci. USA 93, 13170–13175 (1996).
    Article CAS Google Scholar
  29. Capell, A. et al. J. Biol. Chem. 275, 30849–30854 (2000).
    Article CAS Google Scholar
  30. Steiner, H. et al. Biochemistry 38, 14600–14605 (1999).
    Article CAS Google Scholar

Download references

Acknowledgements

We thank M. Delaage and C. Henderson for JLK inhibitors, R. Kopan for mΔENotch-1 and NICD constructs, and the following for antibodies: T. Hartmann and K. Beyreuther for WO2, M. Goedert for BR188, L. Pradier for 9E10, M. Savage for 207, D. Schenk for 10D5C, and T. Tabira and W. Araki for Ab111, Ab333 and Ab444.

Author information

Author notes

  1. Agnès Petit, Frédéric Bihel, Frédéric Checler and Jean-Louis Kraus: These authors contributed equally to this work

Authors and Affiliations

  1. Institut de Pharmacologie Moléculaire et Cellulaire du CNRS, UMR6097, 660 route des Lucioles, Valbonne, 06560, France
    Agnès Petit, Cristine Alvès da Costa & Frédéric Checler
  2. Laboratoire de Chimie Biomoléculaire, Faculté des Sciences de Luminy, Université de la Méditerranée, Marseille, France
    Frédéric Bihel & Jean-Louis Kraus
  3. LGPD Unité Mixte de Recherche 6545, Marseille, France
    Olivier Pourquié

Authors

  1. Agnès Petit
    You can also search for this author inPubMed Google Scholar
  2. Frédéric Bihel
    You can also search for this author inPubMed Google Scholar
  3. Cristine Alvès da Costa
    You can also search for this author inPubMed Google Scholar
  4. Olivier Pourquié
    You can also search for this author inPubMed Google Scholar
  5. Frédéric Checler
    You can also search for this author inPubMed Google Scholar
  6. Jean-Louis Kraus
    You can also search for this author inPubMed Google Scholar

Corresponding authors

Correspondence toFrédéric Checler or Jean-Louis Kraus.

Rights and permissions

About this article

Cite this article

Petit, A., Bihel, F., da Costa, C. et al. New protease inhibitors prevent γ-secretase-mediated production of Aβ40/42 without affecting Notch cleavage.Nat Cell Biol 3, 507–511 (2001). https://doi.org/10.1038/35074581

Download citation

This article is cited by