The Arctic mutation alters helix length and type in the 11–28 β-amyloid peptide monomer—CD, NMR and MD studies in an SDS micelle

The β-amyloid (Aβ) is the major peptide constituent of neuritic plaques in Alzheimer’s disease, 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 Alzheimer’s-like diseases with extensive cerebrovascular pathology. It has been demonstrated that such mutations alter the aggregation ability of Aβ and its neurotoxicity. Among the five mutations at positions 21–23 there is one with distinct clinical characteristics and a potentially distinct pathogenic mechanism—the Arctic (E22G) mutation. We have examined the structures of fragment 11–28 of the native peptide and its E22G variant. This fragment was chosen because it has been shown to be a good model for conformational and aggregation studies as it contains the hydrophobic core responsible for aggregation and the residues critical to α-secretase cleavage of APP. The detailed structure of the two peptides was determined using CD, 2D NMR and molecular dynamics techniques under water–SDS micelle conditions. Our studies indicated the existence of partially α- and 310-helical conformations in the native and mutated peptide, respectively.