Journal article
The Pathogenic A2V Mutant Exhibits Distinct Aggregation Kinetics, Metal Site Structure, and Metal Exchange of the Cu2+ -Aβ Complex
Department of Chemistry, Technical University of Denmark1
NanoChemistry, Department of Chemistry, Technical University of Denmark2
Organic Chemistry, Department of Chemistry, Technical University of Denmark3
University of Copenhagen4
Centre for Catalysis and Sustainable Chemistry, Department of Chemistry, Technical University of Denmark5
A prominent current hypothesis is that impaired metal ion homeostasis may contribute to Alzheimer's disease (AD). We elucidate the interaction of Cu2+ with wild-type (WT) Aβ1–40 and the genetic variants A2T and A2V which display increasing pathogenicity as A2T
Additionally, a rapid, initial, low intensity ThT response is observed, possibly reflecting formation of Cu2+ induced amorphous aggregates, as supported by atomic force microscopy (AFM) and circular dichroism (CD) spectroscopy, again most notably for the A2V variant. Electron paramagnetic resonance (EPR) spectroscopy gives pKa values for transition between two Cu2+ coordination geometries (component I and II) of 7.4 (A2T), 7.9 (WT), and 8.4 (A2V), that is, component I is stabilized at physiological pH in the order A2T
We therefore hypothesize that component I of the Cu–Aβ complex is related to pathogenicity, accounting for both the pathogenic nature of the A2V variant and the protective nature of the A2T variant.
| Language: | English |
|---|---|
| Publisher: | Wiley |
| Year: | 2017 |
| Pages: | 13591-13595 |
| ISSN: | 15213765 , 09476539 , 15213757 and 00448249 |
| Types: | Journal article |
| DOI: | 10.1002/chem.201703440 |
| ORCIDs: | 0000-0001-6123-6875 , 0000-0002-7515-6961 , 0000-0001-6919-1982 , Zhang, Jingdong , Mossin, Susanne , 0000-0002-9241-4352 , 0000-0002-8410-627X , 0000-0002-4667-1112 , 0000-0001-9161-7257 , Kepp, Kasper Planeta and 0000-0002-1823-3035 |
