Aggregation‐Prone Amyloid‐β⋅CuII Species Formed on the Millisecond Timescale under Mildly Acidic Conditions |
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| Authors: | Prof Dr Jeppe T Pedersen Christian B Borg Thomas C T Michaels Dr Tuomas P J Knowles Prof Dr Peter Faller Prof Dr Kaare Teilum Prof Dr Lars Hemmingsen |
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| Affiliation: | 1. Department of Pharmaceutics, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark);2. Department of Biology, University of Copenhagen, Ole Maal?esvej 5, 2200 Copenhagen (Denmark);3. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK);4. Université de Toulouse;5. UPS, INPT 31077 Toulouse (France) and LCC (Laboratoire de Chimie de Coordination), CNRS UPR 8241 205, Route de Narbonne, 31077 Toulouse Cedex 4 (France);6. Department of Chemistry, University of Copenhagen, Universitetsparken 5, 2100 Copenhagen (Denmark) |
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| Abstract: | Metal ions and their interaction with the amyloid beta (Aβ) peptide might be key elements in the development of Alzheimer's disease. In this work the effect of CuII on the aggregation of Aβ is explored on a timescale from milliseconds to days, both at physiological pH and under mildly acidic conditions, by using stopped‐flow kinetic measurements (fluorescence and light‐scattering), 1H NMR relaxation and ThT fluorescence. A minimal reaction model that relates the initial CuII binding and Aβ folding with downstream aggregation is presented. We demonstrate that a highly aggregation prone Aβ ? CuII species is formed on the sub‐second timescale at mildly acidic pH. This observation might be central to the molecular origin of the known detrimental effect of acidosis in Alzheimer's disease. |
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| Keywords: | amyloid beta‐peptides copper kinetics NMR spectroscopy stopped‐flow |
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