Contribution of the Proteasome to the α-Secretase Pathway in Alzheimer’s Disease

  • Philippe Marambaud
  • François Rieunier
  • Sherwin Wilk
  • Jean Martinez
  • Frédéric Checler
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 421)


It has been extensively documented that the β-amyloid precursor protein (βAPP) can undergo several proteolytic cleavages by various secretases, the activity of which leads to the production of either physiological or potentially pathological catabolites1,2. Thus, the concomittant and likely sequential action of β- and γ-secretases ultimately triggers the release of the 39–43 amino-acids long Aβ peptide that corresponds to the main component of the senile plaques invading the cortex in late stages of Alzheimer’s disease neuropathology3,4. An alternative cleavage ascribed to an α-secretase occurs inside the Aβ sequence, thereby generating a secreted C-terminally truncated fragment, APPα2, A dense network of evidences indicates that this catabolite can regulate the activity of serine proteinases involved in blood coagulation and wound repair5,6 but could also fulfill both cytoprotective and neurotrophic cell functions7–9. Interestingly, this a-secretase-derived product is generally accompanied by a down regulation of the production of Aβ2. Thus, it has been well established that effectors targeting the protein kinase C (PKC) enhance the APPα secretion and concomittantly decrease the Aβ production10–13. It is therefore of interest to identify α-secretase(s) candidates, the activators of which could ultimately lower the formation of Aβ. Here, we present evidences of a phosphorylation-dependent contribution of the proteasome to the α-secretase pathway in human cells.


Senile Plaque HK293 Cell Baculoviral Vector Human Kidney Cell Alternative Cleavage 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Selkoe D.J. (1994) Annu. Rev. Neurosci. 17, 489–517.PubMedCrossRefGoogle Scholar
  2. 2.
    Checler F. (1995) J. Neurochem. 65, 1431–1444.CrossRefGoogle Scholar
  3. 3.
    Glenner G.G. and Wong C.W. (1984) Biochem. Biophys. Res. Commun 120 (3). 885–890.PubMedCrossRefGoogle Scholar
  4. 4.
    Masters C.L., Simons G., Weinman N.A., Multhaup G., Mc Donald B.L. and Beyreuther K. (1985) Proc. Natl. Acad. Sci. USA 82, 4245–4249.PubMedCrossRefGoogle Scholar
  5. 5.
    Oltersdorf T., Fritz L.C., Schen D.B., Lieberburg I., Johnson-Wood K.L.. Beattie E.C.. Ward P.J., Blachen R.W.. Dovey H.F. and Sinha S. (1989) Nature 341, 144–147.PubMedCrossRefGoogle Scholar
  6. 6.
    Smith R.P., Higuchi D.A. and Braze G.J. (1990) Science 248, 1126–1128.PubMedCrossRefGoogle Scholar
  7. 7.
    Saitoh T., Sundsmo M., Roch J.M., Kimura N., Cole G., Schubert D., Olsterdorf T. and Schenk D.B. (1989) Cell 58, 615–622.PubMedCrossRefGoogle Scholar
  8. 8.
    Mattson M.P., Cheng B.. Culwell A.R., Esch F.S., Lieberburg I. and Rydel R.E. (1993) Neuron 10, 243–254.PubMedCrossRefGoogle Scholar
  9. 9.
    Qiu W.Q., Ferreira A., Miller C., Koo E.H. and Selkoe D.J. (1995) J. Neurose. 15, 2157 216 7.Google Scholar
  10. 10.
    Caporaso L., Gandy S.E., Buxbaum J.D., Ramabhadran T.V. and Greengard P. (1092) Prot Natl. Acad. Sc, USA 89, 3055–3059.CrossRefGoogle Scholar
  11. 11.
    Gillespie S., Golde T.E. and Younkin S.G. (1992) Biochem. Biophys- Res. Commun 187 (3). 1285–1290.PubMedCrossRefGoogle Scholar
  12. 12.
    Hung A.Y., Haass C., Nitsch R.M., Qiu W.Q., Citron M., Wurtman R.J.. Growdon J.H. and Selkoe D.J (1993) J. Biol. Chem. 268 (31), 22959–22962.PubMedGoogle Scholar
  13. 13.
    Buxbaum J.D., Koo E.H. and Greengard P. (1993) Proc. Natl. Acad. Sci. USA 90, 9195–9198.PubMedCrossRefGoogle Scholar
  14. 14.
    Ishiura S., Tsukahara T., Tabira T. and Sugita H. (1989) FEBS Lett. 257, 388–392.PubMedCrossRefGoogle Scholar
  15. 15.
    Kojima L and Omori M. (1992) FEBS Lett. 304, 57–60.PubMedCrossRefGoogle Scholar
  16. 16.
    Mundy D.I. (1994) Biochem. Biophys. Res. Commun 204, 333–341.PubMedCrossRefGoogle Scholar
  17. 17.
    Peirera M.E., Yu B. and Wilk S. (1992) Arch. Biochem. Biophys. 294, 1–8.CrossRefGoogle Scholar
  18. 18.
    Sisodia S. (1992) Proc. Natl. Acad. Sci. USA 89. 6075–6079.PubMedCrossRefGoogle Scholar
  19. 19.
    De Strooper B., Umans L., Van Leuven F. and Van der Berghe H. (1993) J. Cell. Biol. 121, 295–304.CrossRefGoogle Scholar
  20. 20.
    Felsenstein K.M., Hunihan L.W. and Roberts S.B. (1994) Nature Genetics 6, 251–256.PubMedCrossRefGoogle Scholar
  21. 21.
    Chevallier N., Marambaud P., Vizzavona J., Baur C.P., Spillantini M., Fulcrand P., Martinez.1., Goedcri M.. Vincent J.P. and Checler F. (1997) Brain Res. in press.Google Scholar
  22. 22.
    Marambaud P., Wilk S. and Checler F. (1996) J. Neurochem. 67, 2616–2619.CrossRefGoogle Scholar
  23. 23.
    Marambaud P., Chevallier N., Barelli H., Wilk S. and Checler F. (1997) J. Neurochem. 68, in press.Google Scholar
  24. 24.
    Xu H., Sweeney D., Greengard P. and Gandy S. (1996) Proc. Natl. Acad. Sci. USA 93, 4081–4084.PubMedCrossRefGoogle Scholar
  25. 25.
    Fenteany G., Standaert R., Lane W.S., Choi S., Corey E.J. and Schreiber S.L. (1995) Science 268. 726–731.PubMedCrossRefGoogle Scholar
  26. 26.
    Abraham C., Selkoe D.J. and Potter H. (1988) Cell 52, 487–501.PubMedCrossRefGoogle Scholar
  27. 27.
    Gollin PA., Kalaria R.N., Eikelenboom R, Rozemuller A. and Perry G. (1992) Neuroreport 3, 201–203.PubMedCrossRefGoogle Scholar
  28. 28.
    Rivett A.J. (19891J. Biol. Chem. 264,12215–12219.Google Scholar
  29. 29.
    Rechsteiner M., Hoffman L. and Dubiel W. (1993) J. Biol. Chem. 268, 6065–6068.PubMedGoogle Scholar
  30. 30.
    Peters J.-M. (1994) T.I.N.S. 19, 377–382.Google Scholar
  31. 31.
    Ichai, C., Chevallier N., Delaere R, Dournaud P., Epelbaum J., Hauw J.J., and Checler, F. (1994) J. Neurochem. 62, 645–655.PubMedCrossRefGoogle Scholar
  32. 1.
    Bond, J. S., and A. J. Barrett, 1993, Proteolysis and protein turnover, Proceeding of the 9th I(.’OP Meeting. Williamsburg, Virginia, U. S. A., Portland Press Proceedings. page X IV.Google Scholar
  33. 2.
    Hoesch, Kurt, 1921, Emil Fischer. sein Leben und sein Werk, Verlag Chemie, G.m.b.11.. Berlin und Leipzig, 480 pages.Google Scholar
  34. 3.
    Abderhalden. Emil. 1906. Lehrbuch der Physiologischen Chemie, Urbahn und Schwarzenberg, Berlin. Wien, 787 pages.Google Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Philippe Marambaud
    • 1
  • François Rieunier
    • 2
  • Sherwin Wilk
    • 3
  • Jean Martinez
    • 2
  • Frédéric Checler
    • 1
  1. 1.Institut de Pharmacologie Moléculaire et Cellulaire duCNRS UPR 411ValbonneFrance
  2. 2.URA CNRS 1845MontpellierFrance
  3. 3.Department of PharmacologyMount Sinai School of MedicineNew YorkUSA

Personalised recommendations