Study of the Conformational Transition of Aβ(1−42) Using d-Amino Acid Replacement Analogues

Abstract

A critical event in Alzheimer's disease is the transition of Aβ peptides from their soluble forms into disease-associated β-sheet-rich conformers. Structural analysis of a complete d-amino acid replacement set of Aβ(1−42) enabled us to localize in the full-length 42-mer peptide the region responsible for the conformational switch into a β-sheet structure. Although NMR spectroscopy of trifluoroethanol-stabilized monomeric Aβ(1−42) delineated two separated helical domains, only the destabilization of helix I, comprising residues 11−24, caused a transition to a β-sheet structure. This conformational α-to-β switch was directly accompanied by an aggregation process leading to the formation of amyloid fibrils.