Abstract
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.
Highlights
Ab42 and Ab40 are the two primary alloforms of human amyloid b2protein (Ab)
The extra two amino acids of Ab42 peptide are responsible for elevated neurotoxicity and a higher aggregation propensity than the Ab40 peptide[27]
The SMFS analysis of Ab peptides revealed that mutations of the very C2terminal regions caused significant differences in the propensity of the peptides to form transient dimeric species
Summary
Ab42 and Ab40 are the two primary alloforms of human amyloid b2protein (Ab). The two additional C2terminal residues of Ab42 result in elevated neurotoxicity compared with Ab40, but the molecular mechanism underlying this effect remains unclear. We have developed a single2molecule atomic force microscopy (SMFS) approach enabling us to probe and characterize the interactions of the peptides and proteins in transient misfolded conformations[11,12,13,14,15]. The dynamics force spectroscopy (DFS) approach has been quite informative with respect to the lifetimes of transiently formed misfolded dimers (reviewed in[16]) These studies, applied to Ab4012, Ab4214, a2synuclein[13] and Sup3515, revealed that misfolded dimers have an unexpectedly high stability. We demonstrated that the interaction pattern of Ab40 involving N2termini reduces dimers stability These results are discussed in the context of the role of the N2terminus on the global structural reorganization of the misfolded Ab dimers and their aggregation propensity
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