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

The amyloid beta-peptide is the major protein constituent of neuritic plaqu es in Alzheimer's disease. The beta-peptide varies slightly in length and e xists in two predominant forms: (1) the shorter, 40 residue beta-(1-40), fo und mainly in cerebrovascular amyloid; and (2) the longer, 42 residue beta- (1-42), which is the major component in amyloid plaque core deposits. We re port here that the sodium dodecyl sulphate (SDS) micelle, a membrane-mimick ing system for biophysical studies, prevents aggregation of the beta-(1-40) and the beta-(1-42) into the neurotoxic amyloid-like, beta-pleated sheet s tructure, and instead encourages folding into predominantly alpha-helical s tructures at pH 7.2. Analysis of the nuclear Overhauser enhancement (NOE) a nd the alpha H NMR chemical shift data revealed no significant structural d ifferences between the beta-(1-40) and the beta-(1-42). The NMR-derived, th ree-dimensional structure of the beta-(1-42) consists of an extended chain (Asp1-Gly9), two alpha-helices (Tyr10-Val24 and Lys28-Ala42), and a looped region (Gly25-Ser26-Asn27). The most stable alpha-helical regions reside at Gln15-Val24 and Lys28-Val36. The majority of the amide (NH) temperature co efficients were less than 5, indicative of predominately strong NH backbone bonding. The lack of a persistent region with consistently low NH coeffici ents, together with the rapid NH exchange rates in deuterated water and spi n-labeled studies, suggests that the beta-peptide is located at the lipid-w ater interface of the micelle and does not become inbedded within the hydro phobic interior. This result has implications for the circulation of membra ne-bound beta-peptide in biological fluids, and may also facilitate the des ign of amyloid inhibitors to prevent an alpha-helix --> beta-sheet conversi on in Alzheimer's disease. (C) 1999 Academic Press.