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:

Structural conversion of neurotoxic amyloid-β1–42 oligomers to fibrils

Nature Structural & Molecular Biology volume 17, pages 561–567 (2010)Cite this article

Subjects

Abstract

The amyloid-β1–42 (Aβ42) peptide rapidly aggregates to form oligomers, protofibils and fibrils en route to the deposition of amyloid plaques associated with Alzheimer's disease. We show that low-temperature and low-salt conditions can stabilize disc-shaped oligomers (pentamers) that are substantially more toxic to mouse cortical neurons than protofibrils and fibrils. We find that these neurotoxic oligomers do not have the β-sheet structure characteristic of fibrils. Rather, the oligomers are composed of loosely aggregated strands whose C termini are protected from solvent exchange and which have a turn conformation, placing Phe19 in contact with Leu34. On the basis of NMR spectroscopy, we show that the structural conversion of Aβ42 oligomers to fibrils involves the association of these loosely aggregated strands into β-sheets whose individual β-strands polymerize in a parallel, in-register orientation and are staggered at an intermonomer contact between Gln15 and Gly37.

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: Sequence and structure of the monomer unit in Aβ40 and Aβ42 fibrils.
Figure 2: Characterization of Aβ42 oligomers, protofibrils and fibrils.
Figure 3: Parallel and in-register orientation of β-strands in Aβ42 fibrils.
Figure 4: Turn structure in Aβ42 fibrils and neurotoxic oligomers.
Figure 5: β-strands are staggered in Aβ42 fibrils.
Figure 6: Molecular models of Aβ42 oligomers and fibrils.

Similar content being viewed by others

References

  1. Hardy, J. & Selkoe, D.J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Masters, C.L. et al. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl. Acad. Sci. USA 82, 4245–4249 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 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  PubMed  Google Scholar 

  4. Jarrett, J.T., Berger, E.P. & Lansbury, P.T. The carboxy terminus of the β-amyloid protein is critical for the seeding of amyloid formation—implications for the pathogenesis of Alzheimer's disease. Biochemistry 32, 4693–4697 (1993).

    Article  CAS  PubMed  Google Scholar 

  5. Thinakaran, G. & Koo, E.H. Amyloid precursor protein trafficking, processing, and function. J. Biol. Chem. 283, 29615–29619 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Roher, A.E. et al. β-amyloid-(1–42) is a major component of cerebrovascular amyloid deposits—implications for the pathology of Alzheimer-disease. Proc. Natl. Acad. Sci. USA 90, 10836–10840 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Iwatsubo, T., Saido, T.C., Mann, D.M., Lee, V.M. & Trojanowski, J.Q. Full-length amyloid-β (1–42(43)) and amino-terminally modified and truncated amyloid-β 42(43) deposit in diffuse plaques. Am. J. Pathol. 149, 1823–1830 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Burdick, D. et al. Assembly and aggregation properties of synthetic Alzheimer's A4/β amyloid peptide analogs. J. Biol. Chem. 267, 546–554 (1992).

    CAS  PubMed  Google Scholar 

  9. Borchelt, D.R. et al. Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1–42/1–40 ratio in vitro and in vivo. Neuron 17, 1005–1013 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. Eckman, C.B. et al. A new pathogenic mutation in the APP gene (1716V) increases the relative proportion of Aβ42(43). Hum. Mol. Genet. 6, 2087–2089 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Mayeux, R. et al. Plasma amyloid β-peptide 1–42 and incipient Alzheimer's disease. Ann. Neurol. 46, 412–416 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Kirschner, D.A., Abraham, C. & Selkoe, D.J. X-ray-diffraction from intraneuronal paired helical filaments and extraneuronal amyloid fibers in Alzheimer-disease indicates cross-β conformation. Proc. Natl. Acad. Sci. USA 83, 503–507 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Olofsson, A., Sauer-Eriksson, A.E. & Ohman, A. The solvent protection of Alzheimer amyloid-β-(1–42) fibrils as determined by solution NMR spectroscopy. J. Biol. Chem. 281, 477–483 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Lührs, T. et al. 3D structure of Alzheimer's amyloid-β(1–42) fibrils. Proc. Natl. Acad. Sci. USA 102, 17342–17347 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Balbach, J.J. et al. Supramolecular structure in full-length Alzheimer's β-amyloid fibrils: evidence for a parallel β-sheet organization from solid-state nuclear magnetic resonance. Biophys. J. 83, 1205–1216 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Antzutkin, O.N., Leapman, R.D., Balbach, J.J. & Tycko, R. Supramolecular structural constraints on Alzheimer's β-amyloid fibrils from electron microscopy and solid-state nuclear magnetic resonance. Biochemistry 41, 15436–15450 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Torok, M. et al. Structural and dynamic features of Alzheimer's Aβ peptide in amyloid fibrils studied by site-directed spin labeling. J. Biol. Chem. 277, 40810–40815 (2002).

    Article  PubMed  Google Scholar 

  18. Masuda, Y. et al. Verification of the C-terminal intramolecular β-sheet in Aβ42 aggregates using solid-state NMR: implications for potent neurotoxicity through the formation of radicals. Bioorg. Med. Chem. Lett. 18, 3206–3210 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Tycko, R. Molecular structure of amyloid fibrils: insights from solid-state NMR. Q. Rev. Biophys. 39, 1–55 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Paravastua, A.K., Leapman, R.D., Yau, W.M. & Tycko, R. Molecular structural basis for polymorphism in Alzheimer's β-amyloid fibrils. Proc. Natl. Acad. Sci. USA 105, 18349–18354 (2008).

    Article  Google Scholar 

  21. McLean, C.A. et al. Soluble pool of Aβ amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann. Neurol. 46, 860–866 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Lue, L.F. et al. Soluble amyloid β peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am. J. Pathol. 155, 853–862 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hsia, A.Y. et al. Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. Proc. Natl. Acad. Sci. USA 96, 3228–3233 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Walsh, D.M. et al. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535–539 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Lesne, S. et al. A specific amyloid-β protein assembly in the brain impairs memory. Nature 440, 352–357 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Caughey, B. & Lansbury, P.T. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu. Rev. Neurosci. 26, 267–298 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Glabe, C.G. Common mechanisms of amyloid oligomer pathogenesis in degenerative disease. Neurobiol. Aging 27, 570–575 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. McGowan, E. et al. Aβ42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron 47, 191–199 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chen, Y.R. & Glabe, C.G. Distinct early folding and aggregation properties of Alzheimer amyloid-β peptides Aβ40 and Aβ42 - stable trimer or tetramer formation by Aβ42. J. Biol. Chem. 281, 24414–24422 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Barghorn, S. et al. Globular amyloid β-peptide1–42 oligomer—a homogenous and stable neuropathological protein in Alzheimer's disease. J. Neurochem. 95, 834–847 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Bitan, G., Vollers, S.S. & Teplow, D.B. Elucidation of primary structure elements controlling early amyloid β-protein oligomerization. J. Biol. Chem. 278, 34882–34889 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Bernstein, S.L. et al. Amyloid-β protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer's disease. Nat. Chem. 1, 326–331 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mastrangelo, I.A. et al. High-resolution atomic force microscopy of soluble Aβ42 oligomers. J. Mol. Biol. 358, 106–119 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Yu, L. et al. Structural characterization of a soluble amyloid β-peptide oligomer. Biochemistry 48, 1870–1877 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Gellermann, G.P. et al. Aβ-globulomers are formed independently of the fibril pathway. Neurobiol. Dis. 30, 212–220 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Chimon, S. et al. Evidence of fibril-like β-sheet structures in a neurotoxic amyloid intermediate of Alzheimer's β-amyloid. Nat. Struct. Mol. Biol. 14, 1157–1164 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Sciarretta, K.L., Gordon, D.J., Petkova, A.T., Tycko, R. & Meredith, S.C.A. β 40-Lactam(D23/K28) models a conformation highly favorable for nucleation of amyloid. Biochemistry 44, 6003–6014 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Tarus, B., Straub, J.E. & Thirumalai, D. Dynamics of Asp23-Lys28 salt-bridge formation in Aβ10–35 monomers. J. Am. Chem. Soc. 128, 16159–16168 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Sato, T. et al. Inhibitors of amyloid toxicity based on β-sheet packing of Aβ40 and Aβ42. Biochemistry 45, 5503–5516 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Eisenberg, D. et al. The structural biology of protein aggregation diseases: fundamental questions and some answers. Acc. Chem. Res. 39, 568–575 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ban, T. et al. Direct observation of Aβ amyloid fibril growth and inhibition. J. Mol. Biol. 344, 757–767 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Frydman-Marom, A. et al. Cognitive-performance recovery of Alzheimer's disease model mice by modulation of early soluble amyloidal assemblies. Angew. Chem. Int. Edn Engl. 48, 1981–1986 (2009).

    Article  CAS  Google Scholar 

  43. Shankar, G.M. et al. Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat. Med. 14, 837–842 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cleary, J.P. et al. Natural oligomers of the amyloid-protein specifically disrupt cognitive function. Nat. Neurosci. 8, 79–84 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Takegoshi, K., Nakamura, S. & Terao, T. 13C-1H dipolar-assisted rotational resonance in magic-angle spinning NMR. Chem. Phys. Lett. 344, 631–637 (2001).

    Article  CAS  Google Scholar 

  46. Crocker, E. et al. Dipolar assisted rotational resonance NMR of tryptophan and tyrosine in rhodopsin. J. Biomol. NMR 29, 11–20 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M. Ziliox for assistance with the NMR spectroscopy and critical reading of the manuscript. This work was supported by grants from the US National Institutes of Health (RO1-AG027317 to SOS and RO1-NS35781 to W.E.V.N.) and the Cure Alzheimer's Fund to W.E.V.N. NMR measurements were supported by US National Institutes of Health-National Science Foundation instrumentation grants (S10 RR13889 and DBI-9977553) and were carried out in part at the New York Structural Biology Center. Electron microscopy experiments were performed at the Central Microscopy Imaging Center, Stony Brook University.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, USA

    Mahiuddin Ahmed, Darryl Aucoin & Steven O Smith

  2. Department of Neurosurgery and Medicine, Stony Brook University, Stony Brook, New York, USA

    Judianne Davis & William E Van Nostrand

  3. Institute for Protein Research, Osaka University, Suita, Osaka, Japan

    Takeshi Sato & Saburo Aimoto

  4. Department of Physics and Astronomy, Stony Brook University, Stony Brook, New York, USA

    Shivani Ahuja

  5. Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA

    James I Elliott

Authors
  1. Mahiuddin Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Judianne Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Darryl Aucoin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takeshi Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shivani Ahuja
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Saburo Aimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. James I Elliott
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. William E Van Nostrand
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Steven O Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.A. contributed to all aspects of the manuscript; D.A. performed FTIR measurements and analysis; S.A. and T.S. performed NMR data acquisition; J.D. and W.E.V.N. performed cell toxicity studies; J.I.E., T.S. and S.A. performed peptide synthesis and purification; S.O.S. was the project leader and helped with the writing of the manuscript.

Corresponding author

Correspondence to Steven O Smith.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Results 1–7 and Supplementary Table 1 (PDF 1906 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ahmed, M., Davis, J., Aucoin, D. et al. Structural conversion of neurotoxic amyloid-β1–42 oligomers to fibrils. Nat Struct Mol Biol 17, 561–567 (2010). https://doi.org/10.1038/nsmb.1799

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsmb.1799

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