Amyloid β-peptide is produced by cultured cells during normal metabolism (original) (raw)

Nature volume 359, pages 322–325 (1992)Cite this article

Abstract

ALZHEIMER'S disease is characterized by the extracellular deposition in the brain and its blood vessels of insoluble aggregates of the amyloid β-peptide (Aβ), a fragment, of about 40 amino acids in length, of the integral membrane protein β-amyloid precursor protein (β-APP)1. The mechanism of extracellular accumulation of αβ in brain is unknown and no simple in vitro or in vivo model systems that produce extracellular Aβ have been described. We report here the unexpected identification of the 4K (_M_r 4,000) Aβ and a truncated form of Aβ (∼3K) in media from cultures of primary cells and untransfected and β-APP-transfected cell lines grown under normal conditions. These peptides were immunoprecipitated readily from culture medium by Aβ-specific antibodies and their identities confirmed by sequencing. The con-cept that pathological processes are responsible for the production of Aβ must now be reassessed in light of the observation that Aβ is produced in soluble form in vitro and _in vivo_2 during normal cellular metabolism. Further, these findings provide the basis for using simple cell culture systems to identify drugs that block the formation or release of Aβ, the primary protein constituent of the senile plaques of Alzheimer's disease.

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

Access options

Subscribe to this journal

Receive 51 print issues and online access

$199.00 per year

only $3.90 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

References

  1. Kang, J. et al. Nature 325, 733–736 (1987).
    Article ADS CAS Google Scholar
  2. Seubert, P. et al. Nature 359, 325–327 (1992).
    Article ADS CAS Google Scholar
  3. Selkoe, D. et al. Proc. natn. Acad. Sci. U.S.A. 85, 7341–7345 (1988).
    Article ADS CAS Google Scholar
  4. Tamaoka, A., Kalaria, R. N., Lieberburg, I. & Selkoe, D. J. Proc. natn. Acad. Sci. U.S.A. 89, 1345–1349 (1992).
    Article ADS CAS Google Scholar
  5. Weidemann, A. et al. Cell. 57, 115–126 (1989).
    Article CAS Google Scholar
  6. Oltersdorf, T. et al. J. biol. Chem. 265, 4492–4497 (1990).
    CAS PubMed Google Scholar
  7. Esch, F. et al. Science 248, 1122–1124 (1990).
    Article ADS CAS Google Scholar
  8. Sisodia, S. S., Koo, E. H., Beyreuther, K., Unterbeck, A. & Price, D. L. Science 248, 492–495 (1990).
    Article ADS CAS Google Scholar
  9. Greenberg, S. M., Rosenthal, D. S., Greeley, T. A., Tantravahi, R. & Handin, R. I. Blood 72, 1968–1977 (1988).
    CAS PubMed Google Scholar
  10. Podlisny, M. B., Tolan, D. & Selkoe, D. J. Am. J. Path. 139, 1423–1435 (1991).
    Google Scholar
  11. Estus, S. et al. Science 255, 726–728 (1992).
    Article ADS CAS Google Scholar
  12. Nordstedt, C. et al. Proc. natn. Acad. Sci. U.S.A. 88, 8910–8914 (1991).
    Article ADS CAS Google Scholar
  13. Golde, T., Esius, S., Younkin, L. H., Selkoe, D. J. & Younkln, S. G. Science 255, 728–730 (1992).
    Article ADS CAS Google Scholar
  14. Haass, C., Koo, E. H., Mellon, A., Hung, A. Y. & Selkoe, D. J. Nature 357, 500–503 (1992).
    Article ADS CAS Google Scholar
  15. Gabuzda, D. H., Busciglio, J. & Yankner, B. A. Neurology (abstr.) 42, 304 (1992).
    Google Scholar
  16. Joachim, C. L., Mori, H. & Selkoe, D. J. Nature 341, 226–230 (1989).
    Article ADS CAS Google Scholar
  17. Selkoe, D. J. Neurobiol. Aging 10, 387–395 (1989).
    Article CAS Google Scholar
  18. Mori, H., Takio, K., Ogawara, M. & Selkoe, D. J. J. biol. Chem. 267, 17082–17086 (1992).
    CAS PubMed Google Scholar
  19. Haass, C., Hung, A. Y. & Selkoe, D. J. J. Neurosci. 11, 3783–3793 (1991).
    Article CAS Google Scholar
  20. Anderson, J. P., Chen, Y., Kim, K. S. & Robakis, N. K. J. Neurochem. (in the press).

Download references

Author information

Author notes

  1. Michael G. Schlossmacher
    Present address: Institute of Neurology, Austrian Academy of Sciences, A-1010, Vienna, Austria
  2. Carmen Vigo-Pelfrey, Ivan Lieberburg and Dale Schenk: Athena Neurosciences Inc., 800F Gateway Boulevard, South San Francisco, California 94090, USA
  3. Christian Haass and Michael G. Schlossmacher: C.H. and M.G.S. made equal contributions to this work.

Authors and Affiliations

  1. Department of Neurology and Program in Neuroscience, Harvard Medical School, and Center for Neurologic Diseases, Department of Medicine (Neurology), Brigham and Women's Hospital, Boston, Massachusetts, 02155, USA
    Christian Haass, Michael G. Schlossmacher, Albert Y. Hung, Carmen Vigo-Pelfrey, Angela Mellon, Beth L. Ostaszewski, Ivan Lieberburg, Edward H. Koo, Dale Schenk, David B. Teplow & Dennis J. Selkoe

Authors

  1. Christian Haass
    You can also search for this author inPubMed Google Scholar
  2. Michael G. Schlossmacher
    You can also search for this author inPubMed Google Scholar
  3. Albert Y. Hung
    You can also search for this author inPubMed Google Scholar
  4. Carmen Vigo-Pelfrey
    You can also search for this author inPubMed Google Scholar
  5. Angela Mellon
    You can also search for this author inPubMed Google Scholar
  6. Beth L. Ostaszewski
    You can also search for this author inPubMed Google Scholar
  7. Ivan Lieberburg
    You can also search for this author inPubMed Google Scholar
  8. Edward H. Koo
    You can also search for this author inPubMed Google Scholar
  9. Dale Schenk
    You can also search for this author inPubMed Google Scholar
  10. David B. Teplow
    You can also search for this author inPubMed Google Scholar
  11. Dennis J. Selkoe
    You can also search for this author inPubMed Google Scholar

Rights and permissions

About this article

Cite this article

Haass, C., Schlossmacher, M., Hung, A. et al. Amyloid β-peptide is produced by cultured cells during normal metabolism.Nature 359, 322–325 (1992). https://doi.org/10.1038/359322a0

Download citation

This article is cited by