Journal of Neuroimmune Pharmacology

, Volume 8, Issue 1, pp 262–273

Nanoprobing of the Effect of Cu2+ Cations on Misfolding, Interaction and Aggregation of Amyloid β Peptide

  • Zhengjian Lv
  • Margaret M. Condron
  • David B. Teplow
  • Yuri L. Lyubchenko
ORIGINAL ARTICLE

DOI: 10.1007/s11481-012-9416-6

Cite this article as:
Lv, Z., Condron, M.M., Teplow, D.B. et al. J Neuroimmune Pharmacol (2013) 8: 262. doi:10.1007/s11481-012-9416-6

Abstract

Misfolding and aggregation of the amyloid β-protein (Aβ) are hallmarks of Alzheimer’s disease. Both processes are dependent on the environmental conditions, including the presence of divalent cations, such as Cu2+. Cu2+ cations regulate early stages of Aβ aggregation, but the molecular mechanism of Cu2+ regulation is unknown. In this study we applied single molecule AFM force spectroscopy to elucidate the role of Cu2+ cations on interpeptide interactions. By immobilizing one of two interacting Aβ42 molecules on a mica surface and tethering the counterpart molecule onto the tip, we were able to probe the interpeptide interactions in the presence and absence of Cu2+ cations at pH 7.4, 6.8, 6.0, 5.0, and 4.0. The results show that the presence of Cu2+ cations change the pattern of Aβ interactions for pH values between pH 7.4 and pH 5.0. Under these conditions, Cu2+ cations induce Aβ42 peptide structural changes resulting in N-termini interactions within the dimers. Cu2+ cations also stabilize the dimers. No effects of Cu2+ cations on Aβ-Aβ interactions were observed at pH 4.0, suggesting that peptide protonation changes the peptide-cation interaction. The effect of Cu2+ cations on later stages of Aβ aggregation was studied by AFM topographic images. The results demonstrate that substoichiometric Cu2+ cations accelerate the formation of fibrils at pH 7.4 and 5.0, whereas no effect of Cu2+ cations was observed at pH 4.0. Taken together, the combined AFM force spectroscopy and imaging analyses demonstrate that Cu2+ cations promote both the initial and the elongation stages of Aβ aggregation, but protein protonation diminishes the effect of Cu2+.

Keywords

Amyloid β-protein, Aβ42Alzheimer’s diseaseCu2+ cationsSingle molecule force spectroscopyAtomic force microscopy imaging

Supplementary material

11481_2012_9416_MOESM1_ESM.doc (4.5 mb)
ESM 1The estimation of contour length of all tethers; the force spectroscopy results in the presence and absence of Cu2+ cations at pH 6.8 and 6.0. This material is available free of charge via the Internet. (DOC 4609 kb)

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Zhengjian Lv
    • 1
  • Margaret M. Condron
    • 2
  • David B. Teplow
    • 2
    • 3
  • Yuri L. Lyubchenko
    • 1
  1. 1.Department of Pharmaceutical SciencesUniversity of Nebraska Medical CenterOmahaUSA
  2. 2.Department of NeurologyDavid Geffen School of Medicine at UCLALos AngelesUSA
  3. 3.Molecular Biology and Brain Research Institutes, and Mary S. Easton Center for Alzheimer’s Disease Research at UCLADavid Geffen School of Medicine at UCLALos AngelesUSA