Solution structures of micelle-bound amyloid β-(1-40) and β-(1-42) peptides of Alzheimer’s disease

Abstract

The amyloid β-peptide is the major protein constituent of neuritic plaques in Alzheimer’s disease. The β-peptide varies slightly in length and exists in two predominant forms: (1) the shorter, 40 residue β-(1-40), found mainly in cerebrovascular amyloid; and (2) the longer, 42 residue β-(1-42), which is the major component in amyloid plaque core deposits. We report here that the sodium dodecyl sulphate (SDS) micelle, a membrane-mimicking system for biophysical studies, prevents aggregation of the β-(1-40) and the β-(1-42) into the neurotoxic amyloid-like, β-pleated sheet structure, and instead encourages folding into predominantly α-helical structures at pH 7.2. Analysis of the nuclear Overhauser enhancement (NOE) and the αH NMR chemical shift data revealed no significant structural differences between the β-(1-40) and the β-(1-42). The NMR-derived, three-dimensional structure of the β-(1-42) consists of an extended chain (Asp1-Gly9), two α-helices (Tyr10-Val24 and Lys28-Ala42), and a looped region (Gly25-Ser26-Asn27). The most stable α-helical regions reside at Gln15-Val24 and Lys28-Val36. The majority of the amide (NH) temperature coefficients were less than 5, indicative of predominately strong NH backbone bonding. The lack of a persistent region with consistently low NH coefficients, together with the rapid NH exchange rates in deuterated water and spin-labeled studies, suggests that the β-peptide is located at the lipid-water interface of the micelle and does not become inbedded within the hydrophobic interior. This result has implications for the circulation of membrane-bound β-peptide in biological fluids, and may also facilitate the design of amyloid inhibitors to prevent an α-helix→β-sheet conversion in Alzheimer’s disease.