ß-Hairpin Alignment Alters Oligomer Formation in Aß-Derived Peptides.

ABSTRACT

Amyloid-ß (Aß) forms heterogeneous oligomers, which are implicated in the pathogenesis of Alzheimer's disease (AD). Many Aß oligomers consist of ß-hairpin building blocks─Aß peptides in ß-hairpin conformations. ß-Hairpins of Aß can adopt a variety of alignments, but the role that ß-hairpin alignment plays in the formation and heterogeneity of Aß oligomers is poorly understood. To explore the effect of ß-hairpin alignment on the oligomerization of Aß peptides, we designed and studied two model peptides with two different ß-hairpin alignments. Peptides Aßm17-36 and Aßm17-35 mimic two different ß-hairpins that Aß can form, the Aß17-36 and Aß17-35 ß-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, Aßm17-36 forms triangular trimers that further assemble to form hexamers, while Aßm17-35 forms tetrameric ß-barrels. In SDS-PAGE, Aßm17-36 assembles to form a ladder of oligomers, while Aßm17-35 either assembles to form a dimer or does not assemble at all. The differences in the behavior of Aßm17-36 and Aßm17-35 suggest ß-hairpin alignment as a source of the observed heterogeneity of Aß oligomers.