Aggregation-Prone Amyloid-Cu-II Species Formed on the Millisecond Timescale under Mildly Acidic Conditions

作者：Pedersen Jeppe T^*; Borg Christian B; Michaels Thomas C T; Knowles Tuomas P J; Faller Peter; Teilum Kaare; Hemmingsen Lars

来源：ChemBioChem, 2015, 16(9): 1293-1297.

DOI：10.1002/cbic.201500080

• amyloid beta-peptides
• copper
• kinetics
• NMR spectroscopy
• stopped-flow

Metal ions and their interaction with the amyloid beta (A) peptide might be key elements in the development of Alzheimer's disease. In this work the effect of Cu-II on the aggregation of A 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), H-1 NMR relaxation and ThT fluorescence. A minimal reaction model that relates the initial Cu-II binding and A folding with downstream aggregation is presented. We demonstrate that a highly aggregation prone ACu(II) 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.

• 出版日期2015-6-15