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Cu2+ and AD oligomers - published by Prana scientists

  1. interestingtome

    1,847 Posts.
    Small Angle x-ray Scattering

    Tim M Ryan, Nigel Kirby, Chi L. L. Pham, Blaine R Roberts, Haydyn Mertens, Kevin Jeffrey Barnham, Roberto Cappai, Colin Masters and Cyril C. Curtain

    Metallomics, 2015, Accepted Manuscript

    DOI: 10.1039/C4MT00323C​
    Received 04 Dec 2014, Accepted 09 Feb 2015
    First published online 09 Feb 2015


    Research into causes of Alzheimer’s disease and its treatment has produced tantalising array of hypotheses about the role of transition metal dyshomeostasis, many of them on the interaction of these metals with the neurotoxic amyloid-β peptide (Aβ). Here, we have used small angle X-ray scattering (SAXS) to study the effect of the molar ratio, Cu2+/ Aβ, on the early three-dimensional structures of the Aβ1-40 and Cu2+/ Aβ1-42 peptides in solution. We found that at molar ratios of 0.5 copper to peptide Aβ1-40 aggregated, while Aβ1-42 adopted a relatively monodisperse cylindrical shape, and at a ratio of 1.5 copper to peptide Aβ1-40 adopted a monodisperse cylindrical shape, while Aβ1-42 adopted the shape of an ellipsoid of rotation. We also found, via in-line rapid mixing SAXS analysis, that both peptides in the absence of copper were monodisperse at very short timeframes (<2 sec). Kratky plots of these scattering profiles indicated that immediately after mixing both were intrinsically disordered. Ensemble optimisation modelling reflected this, indicating a wide range of structural conformers. These data reflect the ensembles from which the Cu2+-promoted oligomers were derived. Our results are discussed in the light of other studies that have shown that the Cu2+/ Aβ has a marked effect on fibril and oligomer formation by this peptide, with a higher ratio favouring the formation of cytotoxic non-amyloid oligomers. Our results are relatively consistent with previous two-dimensional studies of the conformations of these Cu2+- induced entities, made on a much longer time-scale than SAXS, by transmission electron microscopy and atomic force microscopy, which showed that a range of oligomeric species are formed. We propose that SAXS carried out on a modern synchrotron beamline enables studies on initial events in disordered protein folding on physiologically-relevant time-scales, and will likely provide great insight into the initiating processes of the Aβ misfolding, oligomerisation and amyloid formation.

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