NMR structure of the Arctic mutation of the Alzheimer's Aβ(1-40) peptide docked to SDS micelles

The Arctic point mutation of the Alzheimer's amyloid beta-peptide is a rare mutation leading to an early onset of Alzheimer's disease. The peptide may interact with neuronal membranes, where it can provide its toxic effects. We used 2D NMR spectroscopy to investigate the conformation of the Arctic mutant of A beta 1-40 Alzheimer's amyloid peptide in sodium dodecyl sulfate micelle solutions, which are the type of amphiphilic structures mimicking some properties of biomembranes. The study showed that the Arctic mutant of A beta 1-40 interacts with the surface of SDS micelles mainly through the Leu17-Asn27 3(10)-helical region, while the Ile31-Val40 region is buried in the hydrophobic interior of the micelle. In contrast, wildtype A beta 1-40 interacts with SDS micelles through the Lys16-Asp23 alpha-helical region and Gly29-Met35. Both the Arctic mutant and the wild-type A beta 1-40 peptides interactions with SDS micelles are hydrophobic in nature. A beta peptides are thought to be capable of forming pores in biomembranes that can cause changes in neuronal and endothelial cell membrane permeability. It has also been shown that A beta peptides containing the Arctic mutation are more neurotoxic and aggregate more readily than the wildtype A beta peptides at physiological conditions. Here, we propose that the extension of the helical structure of Leu17-Asn27 and a high aliphaticity (neutrality) of the C-terminal region in the Arctic A beta peptides are consistent with the idea that formation of ion-permeable pores by A beta oligomers may be one of prevailing mechanisms of a larger neuronal toxicity of the Arctic A beta compared to the wild-type A beta peptides, independent of oxidative damage and lipid peroxidation. (C) 2014 Elsevier B.V. All rights reserved.