Document Detail

Nanoprobing of the effect of Cu(2+) cations on misfolding, interaction and aggregation of amyloid β peptide.
MedLine Citation:
PMID:  23143330     Owner:  NLM     Status:  MEDLINE    
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+).
Zhengjian Lv; Margaret M Condron; David B Teplow; Yuri L Lyubchenko
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-11-11
Journal Detail:
Title:  Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology     Volume:  8     ISSN:  1557-1904     ISO Abbreviation:  J Neuroimmune Pharmacol     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-28     Completed Date:  2013-08-16     Revised Date:  2014-03-07    
Medline Journal Info:
Nlm Unique ID:  101256586     Medline TA:  J Neuroimmune Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  262-73     Citation Subset:  IM    
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MeSH Terms
Aluminum Silicates
Amino Acid Sequence
Amyloid beta-Peptides / chemistry,  drug effects*
Cations / pharmacology
Copper / pharmacology*
Data Interpretation, Statistical
Hydrogen-Ion Concentration
Microscopy, Atomic Force
Molecular Sequence Data
Neurofibrillary Tangles / pathology
Peptide Fragments / chemistry
Proteostasis Deficiencies / pathology*
Grant Support
Reg. No./Substance:
0/Aluminum Silicates; 0/Amyloid beta-Peptides; 0/Buffers; 0/Cations; 0/Peptide Fragments; 0/amyloid beta-protein (1-42); 12001-26-2/mica; 789U1901C5/Copper

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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