The major protein constituent of amyloid deposits in Alzheimer's disease is the β-peptide, which in solution can fold as a random coil, monomeric α-helix, or oligomeric β-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 α-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 β-peptide [β-(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 αH chemical shifts showed that at pH 2−3 there are two α-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 α-helix forms in DPC, whereas the Tyr10−Lys28 helix remained α-helical in SDS up to pH 9.5. With DTAC, the α-helix formed at high pH, and below pH 4 only random coil was present. Most importantly, the present data demonstrate that micelles prevent formation of the toxic β-sheet structure for the 1−28 region, which may eventually have therapeutic implications for the treatment of Alzheimer's disease.

The aggregation of the β-peptide into amyloid is a key pathological event in Alzheimer's disease. This process (β-amyloidosis) involves the conversion of soluble random coil, α-helical or β-sheet conformations into insoluble, aggregated β-pleated sheet structures. The pH is a significant extrinsic factor that influences β-amyloidosis, which must be related to the presence of ionizable groups in the β-peptide. To further evaluate this effect, we determined the dissociation constants (pK a) of the side chains for the aspartic acid (Asp), glutamic acid (Glu), histidine (His), and tyrosine (Tyr) amino acid residues using NMR spectroscopy. The measurements were performed under different solution conditions, where the predominant conformation is either random coil or α-helix. We have used a peptide fragment that comprises residues 1−28 [β-(1−28)] of the natural β-(1−40) or β-(1−42) peptides, which is an appropriate model since the remaining 29−40 or 29−42 regions are devoid of polar and charged amino acid residues. The results demonstrate that the Glu and His residues have larger pK a values in sodium dodecyl sulfate solution, suggesting that electrostatic interactions are important in stabilizing the α-helix and preventing an α-helix → β-sheet rearrangement. A mechanism involving unfavorable interactions of the charged groups with the α-helix macrodipole is proposed for the pH-induced α-helix → β-sheet transformation in water−trifluoroethanol solution.

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