TY - JOUR
T1 - Aggregation prone amyloid-β⋅CuII Species formed on the millisecond timescale at mildly acidic conditions
AU - Pedersen, Jeppe Trudslev
AU - Borg, Christian Bernsen
AU - Michaels, Thomas C. T.
AU - Knowles, Tuomas P. J.
AU - Faller, Peter
AU - Teilum, Kaare
AU - Hemmingsen, Lars Bo Stegeager
PY - 2015/6/1
Y1 - 2015/6/1
N2 - 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. Amyloid-β-CuII interaction kinetics: Copper(II)-containing amyloid plaques might be associated with Alzheimer's disease. To elucidate the mechanism of CuII-induced aggregation of amyloid-β (Aβ), it is important to understand how binding and folding events on the sub-second timescale translate into aggregation events on the hour timescale.
AB - 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. Amyloid-β-CuII interaction kinetics: Copper(II)-containing amyloid plaques might be associated with Alzheimer's disease. To elucidate the mechanism of CuII-induced aggregation of amyloid-β (Aβ), it is important to understand how binding and folding events on the sub-second timescale translate into aggregation events on the hour timescale.
U2 - 10.1002/cbic.201500080
DO - 10.1002/cbic.201500080
M3 - Journal article
C2 - 25989377
SN - 1439-4227
VL - 16
SP - 1293
EP - 1297
JO - ChemBioChem
JF - ChemBioChem
IS - 9
ER -