NDLI: Nanoprobing of the Effect of Cu$^{2+}$ Cations on Misfolding, Interaction and Aggregation of Amyloid β Peptide

Content Provider	Springer Nature Link
Author	Lv, Zhengjian Condron, Margaret M. Teplow, David B. Lyubchenko, Yuri L.
Copyright Year	2012
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 Cu$^{2+}$. Cu$^{2+}$ cations regulate early stages of Aβ aggregation, but the molecular mechanism of Cu$^{2+}$ regulation is unknown. In this study we applied single molecule AFM force spectroscopy to elucidate the role of Cu$^{2+}$ 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 Cu$^{2+}$ cations at pH 7.4, 6.8, 6.0, 5.0, and 4.0. The results show that the presence of Cu$^{2+}$ cations change the pattern of Aβ interactions for pH values between pH 7.4 and pH 5.0. Under these conditions, Cu$^{2+}$ cations induce Aβ42 peptide structural changes resulting in N-termini interactions within the dimers. Cu$^{2+}$ cations also stabilize the dimers. No effects of Cu$^{2+}$ cations on Aβ-Aβ interactions were observed at pH 4.0, suggesting that peptide protonation changes the peptide-cation interaction. The effect of Cu$^{2+}$ cations on later stages of Aβ aggregation was studied by AFM topographic images. The results demonstrate that substoichiometric Cu$^{2+}$ cations accelerate the formation of fibrils at pH 7.4 and 5.0, whereas no effect of Cu$^{2+}$ cations was observed at pH 4.0. Taken together, the combined AFM force spectroscopy and imaging analyses demonstrate that Cu$^{2+}$ cations promote both the initial and the elongation stages of Aβ aggregation, but protein protonation diminishes the effect of Cu$^{2+}$.
Starting Page	262
Ending Page	273
Page Count	12
File Format	PDF
ISSN	15571890
Journal	Journal of Neuroimmune Pharmacology
Volume Number	8
Issue Number	1
e-ISSN	15571904
Language	English
Publisher	Springer US
Publisher Date	2012-11-11
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Amyloid β-protein, Aβ42 Alzheimer’s disease Cu$^{2+}$ cations Single molecule force spectroscopy Atomic force microscopy imaging Neurosciences Immunology Pharmacology/Toxicology Virology Cell Biology
Content Type	Text
Resource Type	Article
Subject	Neuroscience Immunology and Allergy Pharmacology Immunology

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