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.
Amyloid beta-Peptides, Humans, Microscopy, Atomic Force, Protein Folding, Protein Multimerization
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Lv, Zhengjian; Roychaudhuri, Robin; Condron, Margaret M; Teplow, David B.; and Lyubchenko, Yuri L., "Mechanism of amyloid β-protein dimerization determined using single-molecule AFM force spectroscopy." (2013). Journal Articles: Pharmaceutical Sciences. Paper 16.