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Amyloid-β 2 protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer's disease

  • Author(s): Bernstein, SL
  • Dupuis, NF
  • Lazo, ND
  • Wyttenbach, T
  • Condron, MM
  • Bitan, G
  • Teplow, DB
  • Shea, JE
  • Ruotolo, BT
  • Robinson, CV
  • Bowers, MT
  • et al.

Published Web Location

https://doi.org/10.1038/nchem.247
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 2 protein isoforms of Aβ 240 and Aβ 242 and showed that their oligomer-size distributions are very different. Our results are consistent with previous observations that Aβ 240 and Aβ 242 self-assemble via different pathways and provide a candidate in the Aβ 242 dodecamer for the primary toxic species in Alzheimer's disease. © 2009 Macmillan Publishers Limited. All rights reserved.

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