Solution structure model of residues 1-28 of the amyloid β peptide when bound to micelles

The major protein constituent of amyloid deposits in Alzheimer's disease is the alpha-peptide, which in solution can fold as a random coil, monomeric alpha-helix, or oligomeric beta-sheet structure, the latter structure being toxic and eventually precipitating as amyloid. In this report, using circular dichroism and nuclear magnetic resonance spectroscopic techniques, we demonstrate that in micelle solution the alpha-helical structure is the predominate structural motif and that its stability is highly dependent on the pH and the surface charge of the micelle. A peptide fragment comprised of residues 1-28 of the beta-peptide [beta-(1-28)], which occupies the presumed extracellular domain of the amyloid precursor protein and the negatively charged sodium dodecyl sulfate (SDS), the positively charged dodecyltrimethylammonium chloride (DTAC), and the zwitterionic, neutral dodecylphosphocholine (DPC), was utilized. In SDS and DPC, nuclear Overhauser enhancement spectroscopy and the alpha H chemical shifts showed that at pH 2-3 there are two alpha-helical regions located within the Ala2-Asp7 and Tyr10-Lys28 peptide regions. Temperature coefficients for the amide-NH established that the 1-28 region is located at the micelle surface and does not insert into the hydrophobic interior. Above pH 4, no alpha-helix forms in DPC, whereas the Tyr10-Lys28 helix remained alpha-helical in SDS up to pH 9.5. With DTAC, the alpha-helix formed at high pH, and below pH 4 only random coil was present. Most importantly, the present data demonstrate Chat micelles prevent formation of the toxic beta-sheet structure for the 1-28 region, which may eventually have therapeutic implications for the treatment of Alzheimer's disease.