β-Hairpin Alignment Alters Oligomer Formation in Aβ-Derived Peptides

Amyloid-β (Aβ) forms heterogeneous oligomers, which are implicated in the pathogenesis of Alzheimer's disease (AD). Many Aβ oligomers consist of β-hairpin building blocks─Aβ peptides in β-hairpin conformations. β-Hairpins of Aβ can adopt a variety of alignments, but the role that β-hairpin alignment plays in the formation and heterogeneity of Aβ oligomers is poorly understood. To explore the effect of β-hairpin alignment on the oligomerization of Aβ peptides, we designed and studied two model peptides with two different β-hairpin alignments. Peptides Aβm_17-36 and Aβm_17-35 mimic two different β-hairpins that Aβ can form, the Aβ_17-36 and Aβ_17-35 β-hairpins, respectively. These hairpins are similar in composition but differ in hairpin alignment, altering the facial arrangements of the side chains of the residues that they contain. X-ray crystallography and SDS-PAGE demonstrate that the difference in facial arrangement between these peptides leads to distinct oligomer formation. In the crystal state, Aβm_17-36 forms triangular trimers that further assemble to form hexamers, while Aβm_17-35 forms tetrameric β-barrels. In SDS-PAGE, Aβm_17-36 assembles to form a ladder of oligomers, while Aβm_17-35 either assembles to form a dimer or does not assemble at all. The differences in the behavior of Aβm_17-36 and Aβm_17-35 suggest β-hairpin alignment as a source of the observed heterogeneity of Aβ oligomers.