Mechanism of amyloid [beta]-protein dimerization determined using single-molecule AFM force spectroscopy

Aβ42 and Aβ40 are the two primary alloforms of human amyloid β-protein (Aβ). The two additional C-terminal residues of Aβ42 result in elevated neurotoxicity compared with Aβ40, but the molecular mechanism underlying this effect remains unclear. Here, we used single-molecule force microscopy to chara...

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Bibliographic Details
Published in:Scientific reports 2013-10, Vol.3, p.2880
Main Authors: Lv, Zhengjian, Roychaudhuri, Robin, Condron, Margaret M, Teplow, David B, Lyubchenko, Yuri L
Format: Article
Language:English
Subjects:
Alzheimer's disease
Atomic force microscopy
Dimerization
Experiments
Medical research
Microscopy
Monomers
Neurotoxicity
Peptides
Polyethylene glycol
Proteins
Spectroscopy
Spectrum analysis
β-Amyloid
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Summary:Aβ42 and Aβ40 are the two primary alloforms of human amyloid β-protein (Aβ). The two additional C-terminal residues of Aβ42 result in elevated neurotoxicity compared with Aβ40, but the molecular mechanism underlying this effect remains unclear. Here, we used single-molecule force microscopy to characterize interpeptide interactions for Aβ42 and Aβ40 and corresponding mutants. We discovered a dramatic difference in the interaction patterns of Aβ42 and Aβ40 monomers within dimers. Although the sequence difference between the two peptides is at the C-termini, the N-terminal segment plays a key role in the peptide interaction in the dimers. This is an unexpected finding as N-terminal was considered as disordered segment with no effect on the Aβ peptide aggregation. These novel properties of Aβ proteins suggests that the stabilization of N-terminal interactions is a switch in redirecting of amyloids form the neurotoxic aggregation pathway, opening a novel avenue for the disease preventions and treatments.
ISSN:2045-2322
DOI:10.1038/srep02880