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

Abstract

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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Acknowledgements

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). https://doi.org/10.1038/nchem.247

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