The Pathogenic A2V Mutant Exhibits Distinct Aggregation Kinetics, Metal Site Structure, and Metal Exchange of the Cu2+ -Aβ Complex

Arun Kumar Somavarapu, Fei Shen, Kaare Teilum, Jingdong Zhang, Susanne Mossin, Peter W. Thulstrup, Morten J. Bjerrum, Manish K. Tiwari, Daniel Szunyogh, Peter M. Søtofte, Kasper Planeta Kepp, Lars Hemmingsen

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Abstract

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<WT<A2V. Cu2+ significantly extends the lag phase in aggregation kinetics, in particular for the pathogenic A2V variant. 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<WT<A2V. 1H NMR relaxation exhibits the same trend for the non-coordinating aromatic residues (A2T<WT<A2V), and implies markedly faster inter-peptide Cu2+exchange for the A2V variant than for WT and 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.
Original languageEnglish
JournalChemistry: A European Journal
Volume23
Issue number55
Pages (from-to)13591-13595
ISSN0947-6539
DOIs
Publication statusPublished - 2017

Keywords

  • Alzheimer's disease
  • A½myloid beta
  • Copper
  • Kinetics
  • Oligomers

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