Mechanism of amyloid b2protein dimerization determined using single2molecule AFM force

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. Here, we used single2molecule force microscopy to characterize interpeptide interactions for Ab42 and Ab40 and corresponding mutants. We discovered a dramatic difference in the interaction patterns of Ab42 and Ab40 monomers within dimers. Although the sequence difference between the two peptides is at the C2termini, the N2terminal segment plays a key role in the peptide interaction in the dimers. This is an unexpected finding as N2terminal was considered as disordered segment with no effect on the Ab peptide aggregation. These novel properties of Ab proteins suggests that the stabilization of N2terminal interactions is a switch in redirecting of amyloids form the neurotoxic aggregation pathway, opening a novel avenue for the disease preventions and treatments.