Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Amyloid β interacts with the amyloid precursor protein: a potential toxic mechanism in Alzheimer's disease

Nature Neuroscience volume 3, pages 460–464 (2000)Cite this article

Abstract

Amyloid β protein (Aβ) deposition in the brain is a hallmark of Alzheimer's disease (AD). The fibrillar form of Aβ is neurotoxic, although the mechanism of its toxicity is unknown. We showed that conversion of Aβ to the fibrillar form markedly increased binding to specific neuronal membrane proteins, including amyloid precursor protein (APP). Nanomolar concentrations of fibrillar Aβ bound cell-surface holo-APP in cortical neurons. Reduced vulnerability of cultured APP-null neurons to Aβ neurotoxicity suggested that Aβ neurotoxicity involves APP. Thus Aβ toxicity may be mediated by the interaction of fibrillar Aβ with neuronal membrane proteins, notably APP. An Aβ–APP interaction reminiscent of the pathogenic mechanism of prions may thus contribute to neuronal degeneration in AD.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Binding of amyloid fibrils to neuronal membrane proteins and APP.
Figure 2: Conformational dependence of Aβ binding to APP.
Figure 3: Fibrillar Aβ binds predominantly to membrane-bound holo-APP and, to a much lesser extent, to soluble APP.
Figure 4: Aβ neurotoxicity in primary cortical cultures from APP-wild-type and APP-knockout mice.

Similar content being viewed by others

References

  1. Yankner, B.A. Mechanisms of neuronal degeneration in Alzheimer's disease. Neuron 16, 921–932 (1996).

    Article  CAS  Google Scholar 

  2. Selkoe, D.J. Alzheimer's disease: genotypes, phenotypes and treatments. Science 275, 630–631 (1997).

    Article  CAS  Google Scholar 

  3. Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704–706 (1991).

    Article  CAS  Google Scholar 

  4. Citron, M. et al. Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production. Nature 360, 672–674 (1992).

    Article  CAS  Google Scholar 

  5. Suzuki, N. et al. An increased percentage of long amyloid β protein secreted by familial amyloid β protein precursor (βAPP717) mutants. Science 264, 1336–1340 (1994).

    Article  CAS  Google Scholar 

  6. Scheuner, D. et al. Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat. Med. 2, 864–870 (1996).

    Article  CAS  Google Scholar 

  7. Yankner, B. A., Duffy, L. K. & Kirschner, D.A. Neurotrophic and neurotoxic effects of amyloid β protein: reversal by tachykinin neuropeptides. Science 250, 279–282 (1990).

    Article  CAS  Google Scholar 

  8. Pike, C. J., Walencewicz, A. J., Glabe, C. G. & Cotman, C. W. In vitro aging of β-amyloid protein causes peptide aggregation and neurotoxicity. Brain Res. 563, 311–314 (1991).

    Article  CAS  Google Scholar 

  9. Busciglio, J., Lorenzo, A. & Yankner, B. A. Methodological variables in the assessment of β amyloid neurotoxicity. Neurobiol. Aging 13, 609–612 (1992).

    Article  CAS  Google Scholar 

  10. Pike, C. J., Burdick, D., Walencewicz, A. J., Glabe, C. G. & Cotman, C. W. Neurodegeneration induced by β-amyloid peptides in vitro: The role of peptide assembly state. J. Neurosci. 13, 1676–1687 (1993).

    Article  CAS  Google Scholar 

  11. Mattson, M. P., Tomaselli, K. J. & Rydel, R. E. Calcium-destabilizing and neurodegenerative effects of aggregated beta-amyloid peptide are attenuated by basic FGF. Brain Res. 621, 35–49 (1993).

    Article  CAS  Google Scholar 

  12. Lorenzo, A. & Yankner, B. A. Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc. Natl. Acad. Sci. USA 91, 12243–12247 (1994).

    Article  CAS  Google Scholar 

  13. Howlett, D. R. et al. Aggregation state and neurotoxic properties of Alzheimer beta-amyloid peptide. Neurodegeneration 4, 23–32 (1995).

    Article  CAS  Google Scholar 

  14. Geula, G. et al. Aging renders the brain vulnerable to amyloid β-protein neurotoxicity. Nat. Med. 4, 827–831 (1998).

    Article  CAS  Google Scholar 

  15. Behl, C., Davis, J. B., Lesley, R. & Schubert, D. Hydrogen peroxide mediates amyloid β protein toxicity. Cell 77, 817–827 (1994).

    Article  CAS  Google Scholar 

  16. Hensley, K. et al. A model for β-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc. Natl. Acad. Sci. USA 91, 3270–3274 (1994).

    Article  CAS  Google Scholar 

  17. Busciglio, J., Lorenzo, A., Yeh, J. & Yankner, B. A. Beta-amyloid fibrils induce tau phosphorylation and loss of microtubule binding. Neuron 14, 879–888 (1995).

    Article  CAS  Google Scholar 

  18. Zhang, C. et al. Focal adhesion kinase expressed by nerve cell lines shows increased tyrosine phosphorylation in response to Alzheimer's A beta peptide. J. Biol. Chem. 269, 25247–25250 (1994).

    CAS  Google Scholar 

  19. Kang, J. et al. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, 733–736 (1987).

    Article  CAS  Google Scholar 

  20. Schubert, D., Jin, L.-W., Saitoh, T. & Cole, G. The regulation of amyloid β protein precursor secretion and its modulatory role in cell adhesion. Neuron 3, 689–694 (1989).

    Article  CAS  Google Scholar 

  21. Chen, M. & Yankner, B. A. An antibody to β-amyloid and the amyloid precursor protein inhibits cell-substratum adhesion in many mammalian cell types. Neurosci. Lett. 125, 223–226 (1991).

    Article  CAS  Google Scholar 

  22. Breen, K. C., Bruce, M. & Anderton, B. H. Beta amyloid precursor protein mediates neuronal cell-cell and cell-surface adhesion. J. Neurosci. Res. 28, 90–100 (1991).

    Article  CAS  Google Scholar 

  23. Milward, E. A. et al. The amyloid protein precursor of Alzheimer's disease is a mediator of the effects of nerve growth factor on neurite outgrowth. Neuron 9, 129–137 (1992).

    Article  CAS  Google Scholar 

  24. Kibbey, M. C. et al. β-amyloid precursor protein binds to the neurite-promoting IKVAV site of lamin. Proc. Natl. Acad. Sci. USA 90, 10150–10153 (1993).

    Article  CAS  Google Scholar 

  25. Saitoh, T. et al. Secreted form of amyloid β protein precursor is involved in the growth regulation of fibroblasts. Cell 58, 615–622 (1989).

    Article  CAS  Google Scholar 

  26. Mattson, M. P. et al. Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the β-amyloid precursor protein. Neuron 10, 243–254 (1993).

    Article  CAS  Google Scholar 

  27. Schubert, D. & Behl, C. The expression of amyloid beta protein precursor protects nerve cells from β-amyloid and glutamate toxicity and alters their interaction with the extracellular matrix. Brain Res. 629, 275–282 (1993).

    Article  CAS  Google Scholar 

  28. May, P. C., Boggs, L. N. & Fuson, K. S. Neurotoxicity of human amylin in rat primary hippocampal cultures: similarity to Alzheimer's disease amyloid-beta neurotoxicity. J. Neurochem. 61, 2330–2333 (1993).

    Article  CAS  Google Scholar 

  29. Lorenzo, A., Razzaboni, B., Weir, G. C. & Yankner, B. A. Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus. Nature 368, 756–760 (1994).

    Article  CAS  Google Scholar 

  30. Yan, S. D. et al. RAGE and amyloid-βpeptide neurotoxicity in Alzheimer's disease. Nature 382, 685–691 (1996).

    Article  CAS  Google Scholar 

  31. White, A. R. et al. Survival of cultured neurons from amyloid precursor protein knock-out mice against Alzheimer's amyloid-beta toxicity and oxidative stress. J. Neurosci. 18, 6207–6217 (1998).

    Article  CAS  Google Scholar 

  32. Zhen, H. et al. β-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell 81, 525–531 (1995).

    Article  Google Scholar 

  33. White, A. R. et al. The Alzheimer's disease amyloid precursor protein modulates copper-induced toxicity and oxidative stress in primary neuronal cultures. J. Neurosci. 19, 9170–9179 (1999).

    Article  CAS  Google Scholar 

  34. Yoshikawa, K., Aizawa, T. & Hayashi, Y. Degeneration in vitro of post-mitotic neurons overexpressing the Alzheimer amyloid protein precursor. Nature 359, 64–67 (1992).

    Article  CAS  Google Scholar 

  35. Nishimura, I. et al. Degeneration in vivo of rat hippocampal neurons by wild-type Alzheimer amyloid precursor protein overexpressed by adenovirus-mediated gene transfer. J. Neurosci. 18, 2387–2398 (1998).

    Article  CAS  Google Scholar 

  36. Bursztajn, S. et al. Overexpression in neurons of human presenilin-1 or a presenilin-1 familial Alzheimer disease mutant does not enhance apoptosis. J. Neurosci. 18, 9790–9799 (1998).

    Article  CAS  Google Scholar 

  37. Xu, X. et al. Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis. Proc. Natl. Acad. Sci. USA 96, 7547–7552 (1999).

    Article  CAS  Google Scholar 

  38. Uetsuki, T. et al. Activation of neuronal caspase-3 by intracellular accumulation of wild-type Alzheimer amyloid precursor protein. J. Neurosci. 19, 6955–6964 (1999).

    Article  CAS  Google Scholar 

  39. Russo, T. et al. Fe65 and the protein network centered around the cytosolic domain of the Alzheimer's beta-amyloid precursor protein. FEBS Lett. 434, 1–7 (1998).

    Article  CAS  Google Scholar 

  40. Yamatsuji, T. et al. G protein-mediated neuronal DNA fragmentation induced by familial Alzheimer's disease-associated mutants of APP. Science 272, 1349–1352 (1996).

    Article  CAS  Google Scholar 

  41. Perez, R. G., Zheng, H., Van de Ploeg, L. H. T. & Koo, E. H. The β-amyloid precursor protein of Alzheimer's disease enhances neuron viability and modulates neuronal polarity. J. Neurosci. 17, 9407–9414 (1997).

    Article  CAS  Google Scholar 

  42. Bueler H. et al. Mice devoid of PrP are resistant to scrapie. Cell 73, 1339–1347 (1993).

    Article  CAS  Google Scholar 

  43. Brown, D. R., Schmidt, B. & Kretzschmer, H. A. Role of microglia and host prion protein in neurotoxicity of a prion protein fragment. Nature 380, 345–347 (1996).

    Article  CAS  Google Scholar 

  44. Hegde R. S. et al. Transmissible and genetic prion diseases share a common pathway of neurodegeneration. Nature 402, 822–826 (1999).

    Article  CAS  Google Scholar 

  45. Davis-Salinas, J., Saporito-Irwin, S. M., Cotman, C. W. & Van Nostrand W. E. Amyloid beta-protein induces its own production in cultured degenerating cerebrovascular smooth muscle cells. J. Neurochem. 65, 931–934 (1995).

    Article  CAS  Google Scholar 

  46. Yang, A., Chandswangbhuvana, D., Shu, T., Henschen, A., & Glabe, C. G. Intracellular accumulation of insoluble, newly synthesized Aβn-42 in amyloid precursor protein-transfected cells that have been treated with Aβ1-42. J. Biol. Chem. 274, 20650–20656 (1999).

    Article  CAS  Google Scholar 

  47. Paganetti, P. A., Lis, M., Klafki, H. -W. & Staufenbiel, M. Amyloid precursor protein truncated at any of the γ-secretase sites is not cleaved to β-amyloid. J. Neurosci. Res. 46, 283–293 (1996).

    Article  CAS  Google Scholar 

  48. Ledermann, B. & Burki, K. Establishment of a germ-line competent C57BL/6 embryonic stem cell line. Exp. Cell Res. 197, 254–258 (1991).

    Article  CAS  Google Scholar 

  49. Condrescu, M., Osses, L. & DiPolo, R. Partial purification and characterization of the (Ca2+, Mg2+) ATPase from squid optic nerve plasma membrane. Biochem. Biophys. Acta 769, 261–269 (1984).

    Article  CAS  Google Scholar 

  50. Savage, M. R. et al. Turnover of amyloid β-protein in mouse brain and acute reduction of its level by phorbol ester. J. Neurosci. 18, 1743–1752 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH grants (NS30352 and NS33325), a grant from Novartis Pharma, Ltd. and a Zenith Award from the Alzheimer's Association to B.A.Y., grants from Conicet and Conicor to A.L., an NIH training grant to Z.Z. and an NIH MRRC Core grant.

Author information

Authors and Affiliations

  1. Department of Neurology, Harvard Medical School and Division of Neuroscience, The Children's Hospital, Enders 260, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Alfredo Lorenzo, Menglan Yuan, Zhuohua Zhang & Bruce A. Yankner

  2. Instituto de Investigación Médica Mercedes y Martín Ferreyra, Casilla de Correo 389, Córdoba, 5000, Argentina

    Alfredo Lorenzo, Jorge Mautino & Francisco Sol Vigo

  3. Preclinical Research, Novartis Pharma Ltd., Basel, CH-4002, Switzerland

    Paolo A. Paganetti, Christine Sturchler-Pierrat, Matthias Staufenbiel & Bernd Sommer

Authors
  1. Alfredo Lorenzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Menglan Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhuohua Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paolo A. Paganetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christine Sturchler-Pierrat
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Matthias Staufenbiel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jorge Mautino
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Francisco Sol Vigo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bernd Sommer
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bruce A. Yankner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bruce A. Yankner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lorenzo, A., Yuan, M., Zhang, Z. et al. Amyloid β interacts with the amyloid precursor protein: a potential toxic mechanism in Alzheimer's disease. Nat Neurosci 3, 460–464 (2000). https://doi.org/10.1038/74833

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/74833

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing