Conformational solution studies of the SDS micelle‐bound 11‐28 fragment of two Alzheimer's β‐amyloid variants (E22K and A21G) using CD, NMR, and MD techniques

The β‐amyloid (Aβ) is the major peptide constituent of neuritic plaques in Alzheimer's disease (AD) and its aggregation is believed to play a central role in the pathogenesis of the disease. Naturally occurring mutations resulting in changes in the Aβ sequence (pos. 21‐23) are associated with familial AD‐like diseases with extensive cerebrovascular pathology. It was proved that the mutations alter the aggregation ability of Aβ and its neurotoxicity. Among five mutations at positions 21–23 there are two mutations with distinct clinical characteristics and potentially distinct pathogenic mechanism—the Italian (E22K) and the Flemish (A21G) mutations. In our studies we have examined the structures of the 11‐28 fragment of the Italian and Flemish Aβ variants. The fragment was chosen because it has been shown to be the most important for amyloid fibril formation. The detailed structure of both variants Aβ(11‐28) was determined using CD, 2D NMR, and molecular dynamics techniques under water‐SDS micelle conditions. The NMR analysis revealed two distinct sets of proton resonances for the peptides. The studies of both peptides pointed out the existence of well‐defined α‐helical conformation in the Italian mutant, whereas the Flemish was found to be unstructured with the possibility of a bent structure in the central part of the peptide. © 2007 Wiley Periodicals, Inc. Biopolymers 87: 23–39, 2007. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com