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 P. Kepp; Lars Hemmingsen

doi:10.1002/chem.201703440

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 P. Kepp, Lars Hemmingsen

10 Citations (Scopus)

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) Aβ_1–40 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 pK_a 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 language	English
Journal	Chemistry - A European Journal
Volume	23
Issue number	55
Pages (from-to)	13591-13595
Number of pages	5
ISSN	0947-6539
DOIs	https://doi.org/10.1002/chem.201703440
Publication status	Published - 4 Oct 2017

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Somavarapu, A. K., Shen, F., Teilum, K., Zhang, J., Mossin, S., Thulstrup, P. W., Bjerrum, M. J., Tiwari, M. K., Szunyogh, D., Søtofte, P. M., Kepp, K. P., & Hemmingsen, L. (2017). The Pathogenic A2V Mutant Exhibits Distinct Aggregation Kinetics, Metal Site Structure, and Metal Exchange of the Cu²⁺-Aβ Complex. Chemistry - A European Journal, 23(55), 13591-13595. https://doi.org/10.1002/chem.201703440

Somavarapu, AK, Shen, F, Teilum, K, Zhang, J, Mossin, S, Thulstrup, PW , Bjerrum, MJ, Tiwari, MK, Szunyogh, D, Søtofte, PM, Kepp, KP & Hemmingsen, L 2017, 'The Pathogenic A2V Mutant Exhibits Distinct Aggregation Kinetics, Metal Site Structure, and Metal Exchange of the Cu²⁺-Aβ Complex', Chemistry - A European Journal, vol. 23, no. 55, pp. 13591-13595. https://doi.org/10.1002/chem.201703440

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

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.",

author = "Somavarapu, {Arun Kumar} and Fei Shen and Kaare Teilum and Jingdong Zhang and Susanne Mossin and Thulstrup, {Peter W.} and Bjerrum, {Morten J.} and Tiwari, {Manish K.} and Daniel Szunyogh and S{\o}tofte, {Peter M.} and Kepp, {Kasper P.} and Lars Hemmingsen",

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doi = "10.1002/chem.201703440",

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T1 - The Pathogenic A2V Mutant Exhibits Distinct Aggregation Kinetics, Metal Site Structure, and Metal Exchange of the Cu2+-Aβ Complex

AU - Somavarapu, Arun Kumar

AU - Shen, Fei

AU - Teilum, Kaare

AU - Zhang, Jingdong

AU - Mossin, Susanne

AU - Thulstrup, Peter W.

AU - Bjerrum, Morten J.

AU - Tiwari, Manish K.

AU - Szunyogh, Daniel

AU - Søtofte, Peter M.

AU - Kepp, Kasper P.

AU - Hemmingsen, Lars

PY - 2017/10/4

Y1 - 2017/10/4

N2 - 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.

AB - 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.

U2 - 10.1002/chem.201703440

DO - 10.1002/chem.201703440

M3 - Journal article

C2 - 28815875

SN - 0947-6539

VL - 23

SP - 13591

EP - 13595

JO - Chemistry: A European Journal

JF - Chemistry: A European Journal

IS - 55

ER -

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

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