Conformational Effects of the A21G Flemish Mutation on the Aggregation of Amyloid β Peptide

Among the various hereditary mutants of amyloid beta (A beta) in familial Alzheimer's disease (AD), the A21G Flemish-type mutant has unique properties showing a low aggregation propensity but progressive deposition in vascular walls. Moreover, in contrast to other familial AD cases that show extensive A beta(1-42) deposition in the brain, patients with Flemish AD predominantly exhibit the deposition of the A beta(1-40) isoform. Here we report the structural characterization of the Flemish-type mutant (A21G) in comparison with the wild-type A beta(1-40) peptide to examine the possible effects of the A21G mutation on the conformation of the A beta(1-40) isoform. The kinetic analysis of the aggregation of the peptides monitored by thioflavin T fluorescence measurement indicates that the mutation precludes the initial nucleation process of amyloid fibril formation by A beta(1-40). Spectroscopic data indicate that the Flemish-type mutant bound to aqueous micelles composed of lyso-GM1, in which the mobile N-terminal segment is tethered through the C-terminal helical segment, has reduced alpha-helical structure compared to the wild-type peptide. Our findings suggest that the mutational perturbation to the membrane binding properties is coupled with the changes in nucleation behavior of A beta during its fibril formation.