Study of the conformational transition of A beta(1-42) using D-amino acid replacement analogues

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