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

摘要

b -(1-40) and b -(1-42) (40 and 42 residues respectively) are the major protein constituents of amyloid deposits in Alzheimer's disease (AD). Under certain conditions, the b -peptides aggregate and precipitate into b -sheet structures, a process that occurs during amyloid formation.; To provide a molecular basis for the role of biological membranes in amyloid formation, solution structures of b -(1-40) and b -(1-42) were investigated in the sodium dodecyl sulphate (SDS) micelle, a membrane mimicking system for biophysical studies, in which the b -peptides fold into stable a -helical conformations. Analysis of the NMR data revealed no significant structural differences between b -(1-40) and b -(1-42). The three-dimensional structure of b -(1-42) calculated from the NMR data is an flexible extended chain (Asp1-Gly9), two a -helices (Tyr10-Val24 and Lys28-Ala42) and a looped region (Gly25-Asn27). The majority of the amide (NH) temperature coefficients were less than 5, indicative of predominantly strong NH backbone bonding. The lack of a persistent region with consistently low NH coefficients, together with the rapid NH exchange rate in the deuterated water and spin label studies, suggests that the b -peptides are located at the lipid-water interface and do not become embedded within the hydrophobic interior.; The structures of b -(1-40) and b -(1-42) in water solution at neutral pH were also studied by NMR techniques. Detailed analysis of the chemical shift and NOE patterns, together with sedimentation equilibrium and pulsed field gradient diffusion measurements showed that the major structure is a monomeric, random extended chain. Comparison of b -(1-40) and b -(1-42) NMR data revealed differences in that b -(1-42) displayed two NH resonances for the Val36-Val39 region. This doubling of peaks may result from the existence of two conformers that may differ in backbone configuration or differ in potential folding that causes the more pathogenic b -(1-42) peptide to aggregate faster as amyloid.; In conclusion, the detailed structural studies presented here will aid in understanding the mechanism of amyloid formation and facilitate the design of amyloid inhibitors in AD.