Amyloid-β protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer’s disease
By Summer L. Bernstein, N. Dupuis, N. Lazo, T. Wyttenbach, M. Condron, G. Bitan, David B. Teplow, J. Shea, B. Ruotolo, Carol V. Robinson and 1 more. Nature Chemistry, 2009
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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.
Subfields: Molecular Biology, Physiology
View Paper: https://www.semanticscholar.org/paper/9a74bb4f88988878519ef467345cda70e7bd79e6
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Citations in the corpus
- Aβ Oligomers Cause Localized Ca2+ Elevation, Missorting of Endogenous Tau into Dendrites, Tau Phosphorylation, and Destruction of Microtubules and Spines (2010, background): “We also note that in our preparations we did not consistently observe a band at 56 kDa, a species that has been reported to be toxic for transgenic mice (Lesné et al., 2006) but can be visualized in certain conditions (Walsh et al., 2005; Ashe, 2006; Bernstein et al., 2009).”
- Structural conversion of neurotoxic amyloid-β(1–42) oligomers to fibrils (2010, neutral): “Photochemical crosslinking and mass spectrometry have previously found stable pentamers and hexamers in solution 31 , 32 .”