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Amyloid-β protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer's disease


In recent years, small protein oligomers have been implicated in the aetiology of a number of important amyloid diseases, such as type 2 diabetes, Parkinson's disease and Alzheimer's disease. As a consequence, research efforts are being directed away from traditional targets, such as amyloid plaques, and towards characterization of early oligomer states. Here we present a new analysis method, ion mobility coupled with mass spectrometry, for this challenging problem, which allows determination of in vitro oligomer distributions and the qualitative structure of each of the aggregates. We applied these methods to a number of the amyloid-β protein isoforms of Aβ40 and Aβ42 and showed that their oligomer-size distributions are very different. Our results are consistent with previous observations that Aβ40 and Aβ42 self-assemble via different pathways and provide a candidate in the Aβ42 dodecamer for the primary toxic species in Alzheimer's disease.

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Figure 1: Negative-ion mass spectrum and ATDs of Aβ40.
Figure 2: Arrival time distributions.
Figure 3: Aβ42 oligomer distributions.
Figure 4: The normalized cross-sections for the tetramers.
Figure 5: Mechanism of oligomerization and eventual fibril formation for Aβ42 and for Aβ40.

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  1. Meier, J. J. et al. Inhibition of human IAPP fibril formation does not prevent β-cell death: evidence for distinct actions of oligomers and fibrils of human IAPP. Am. J. Physiol. Endocrinol. Metab. 291, E1317–E1324 (2006).

    Article  CAS  Google Scholar 

  2. Conway, K. A. et al. Acceleration of oligomerization, not fibrillization, is a shared property of both α-synuclein mutations linked to early-onset Parkinson's disease: implications for pathogenesis and therapy. Proc. Natl Acad. Sci. USA 97, 571–576 (2000).

    Article  CAS  Google Scholar 

  3. Klein, W. L., Krafft, G. A. & Finch, C. E. Targeting small Aβ oligomers: the solution to an Alzheimer's disease conundrum? Trends Neurosci. 24, 219–224 (2001).

    Article  CAS  Google Scholar 

  4. Kirkitadze, M. D., Bitan, G. & Teplow, D. B. Paradigm shifts in Alzheimer's disease and other neurodegenerative disorders: the emerging role of oligomeric assemblies. J. Neurosci. Res. 69, 567–577 (2002).

    Article  CAS  Google Scholar 

  5. Cheng, I. H. et al. Accelerating amyloid-β fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models. J. Biol. Chem. 282, 23818–23828 (2007).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  7. Lazo, N. D., Maji, S. K., Fradinger, E. A., Bitan, G. & Teplow, D. B. in Amyloid Proteins: The Beta Sheet Conformation and Disease (ed. Sipe, J. D.) 385–491 (Wiley, 2005).

    Google Scholar 

  8. Bitan, G., Lomakin, A. & Teplow, D. B. Amyloid β-protein oligomerization. Prenucleation interactions revealed by photo-induced cross-linking of unmodified proteins. J. Biol. Chem. 276, 35176–35184 (2001).

    Article  CAS  Google Scholar 

  9. 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  Google Scholar 

  10. Bitan, G. et al. Amyloid β-protein (Aβ) assembly: Aβ40 and Aβ42 oligomerize through distinct pathways. Proc. Natl Acad. Sci. USA 100, 330–335 (2003).

    Article  CAS  Google Scholar 

  11. 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  Google Scholar 

  12. Bitan, G., Fradinger, E. A., Spring, S. M. & Teplow, D. B. Neurotoxic protein oligomers – what you see is not always what you get. Amyloid 12, 88–95 (2005).

    Article  Google Scholar 

  13. von Helden, G., Hsu, M.-T., Kemper, P. R. & Bowers, M. T. Structures of carbon cluster ions from 3 to 60 atoms: linears to rings to fullerenes. J. Chem. Phys. 95, 3835–3837 (1991).

    Article  CAS  Google Scholar 

  14. Wyttenbach, T. & Bowers, M. T. Gas-phase conformations: the ion mobility/ion chromatography method. Top. Curr. Chem. 225, 207–232 (2003).

    Article  CAS  Google Scholar 

  15. Bernstein, S. L. et al. Amyloid β-protein: monomer structure and early aggregation states of Aβ42 and its Pro19 alloform. J. Am. Chem. Soc. 127, 2075–2084 (2005).

    Article  CAS  Google Scholar 

  16. Hou, L., Kang, I., Marchant, R. E. & Zagorski, M. G. Methionine 35 oxidation reduces fibril assembly of the amyloid Aβ-(1-42) peptide of Alzheimer's disease. J. Biol. Chem. 277, 40173–40176 (2002).

    Article  CAS  Google Scholar 

  17. Wood, S. J., Wetzel, R., Martin, J. D. & Hurle, M. R. Prolines and amyloidogenicity in fragments of the Alzheimer's peptide β/A4. Biochemistry 34, 724–730 (1995).

    Article  CAS  Google Scholar 

  18. Klein, W. L., Stine, W. B. Jr & Teplow, D. B. Small assemblies of unmodified amyloid β-protein are the proximate neurotoxin in Alzheimer's disease. Neurobiol. Aging 25, 569–580 (2004).

    Article  CAS  Google Scholar 

  19. Bitan, G. et al. A molecular switch in amyloid assembly: Met35 and amyloid β-protein oligomerization. J. Am. Chem. Soc. 125, 15359–15365 (2003).

    Article  CAS  Google Scholar 

  20. Gidden, J., Ferzoco, A., Baker, E. S. & Bowers, M. T. Duplex formation and the onset of helicity in poly d(CG)n oligonucleotides in a solvent-free environment. J. Am. Chem. Soc. 126, 15132–15140 (2004).

    Article  CAS  Google Scholar 

  21. Baumketner, A. et al. Amyloid β-protein monomer structure: a computational and experimental study. Protein Sci. 15, 420–428 (2006).

    Article  CAS  Google Scholar 

  22. Maji, S. K., Amsden, J. J., Rothschild, K. J., Condron, M. M. & Teplow, D. B. Conformational dynamics of amyloid β-protein assembly probed using intrinsic fluorescence. Biochemistry 44, 13365–13376 (2005).

    Article  CAS  Google Scholar 

  23. Wyttenbach, T., von Helden, G., Batka, J. J., Carlat, D. & Bowers, M. T. Effect of the long-range potential on ion mobility measurements. J. Am. Soc. Mass Spectrom. 8, 275–282 (1997).

    Article  CAS  Google Scholar 

  24. Oosawa, F. & Kasai, M. Theory of linear and helical aggregations of macromolecules. J. Mol. Biol. 4, 10–21 (1962).

    Article  CAS  Google Scholar 

  25. Tobacman, L. S. & Korn, E. D. The kinetics of actin nucleation and polymerization. J. Biol. Chem. 258, 3207–3214 (1983).

    CAS  PubMed  Google Scholar 

  26. Sobott, F., Hernandez, H., McCammon, M. G., Tito, M. A. & Robinson, C. V. A tandem mass spectrometer for improved transmission and analysis of large macromolecular assemblies. Anal. Chem. 74, 1402–1407 (2002).

    Article  CAS  Google Scholar 

  27. Ruotolo, B. T. et al. Evidence for macromolecular protein rings in the absence of bulk water. Science 310, 1658–1661 (2005).

    Article  CAS  Google Scholar 

  28. McCammon, M. G., Hernandez, H., Sobott, F. & Robinson, C. V. Tandem mass spectrometry defines the stoichiometry and quaternary structural arrangement of tryptophan molecules in the multiprotein complex TRAP. J. Am. Chem. Soc. 126, 5950–5951 (2004).

    Article  CAS  Google Scholar 

  29. 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  Google Scholar 

  30. Lomakin, A., Chung, D. S., Benedek, G. B., Kirschner, D. A. & Teplow, D. B. On the nucleation and growth of amyloid β-protein fibrils: detection of nuclei and quantitation of rate constants. Proc. Natl Acad. Sci. USA 93, 1125–1129 (1996).

    Article  CAS  Google Scholar 

  31. Wyttenbach, T., Kemper, P. R. & Bowers, M. T. Design of a new electrospray ion mobility mass spectrometer. Int. J. Mass Spectrom. 212, 13–23 (2001).

    Article  CAS  Google Scholar 

  32. Mason, E. A. & McDaniel, E. W. Transport Properties of Ions in Gases (Wiley, 1988).

    Book  Google Scholar 

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M.T.B., G.B. and D.B.T. thank the National Institutes of Health, J.E.S. thanks the National Science Foundation, the Alfred P. Sloan Foundation and the David and Lucile Packard Foundation, and C.V.R. thanks the Biotechnology and Biological Sciences Research Council for support of this work. We gratefully acknowledge C. Carpenter for her help in producing the manuscript and figures.

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S.L.B., N.D.L., G.B., D.B.T., J-E.S. and M.T.B. conceived and designed the experiments, S.L.B. and T.W. carried out the experiments, N.F.D. and T.W. designed and performed the modelling, S.L.B., B.T.F. and C.V.R. measured the highly aggregated mass spectra, M.M.C. synthesized the peptides and M.T.B. wrote the paper.

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Correspondence to Michael T. Bowers.

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

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