Amyloid-β protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer’s disease. Nat Chem

Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106-9510, USA.
Nature Chemistry (Impact Factor: 25.33). 07/2009; 1(4):326-31. DOI: 10.1038/nchem.247
Source: PubMed


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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    • "[5] [6] [7] [8] [9] IMS has provided, for instance, a direct measure for the conformer preferences of solvent-free polypeptides, [10] [11] [12] [13] DNA complexes [14] and large protein complexes [15] [16] as well as oligomerization of protein fragments. [17] [18] Applications of IMS also include the separation of conformers of flexible molecules, such as biopolymers, and the determination of their possible solvent-free rearrangements while reacting with the site of the protein-coupled receptor. [19] Interpretation of IMS data critically relies on conformation search strategies; hence, various simulation methods have been applied to generate low-energy structures and to correlate them with experimentally determined collision cross section (CCS). "
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    • "For instance, mutations that increase hydrophobicity of the Alzheimer's beta peptide Aβ1-42 have a pronounced effect on its aggregation behaviour and the size distribution of the resulting oligomers [23–26, 40], promoting toxicity and expediting the fibrillization process. In the same spirit, two extra hydrophobic residues in Aβ1-42 are believed to contribute to the more pronounced oligomerisation and faster fibrillization compared to its alloform Aβ1- 40 [24] [25] [40]. Temperature, pH, and concentration of certain metals also affect oligomerization and pathways of fibrillization [41] [42] [43] [44]. "
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