SOLUTION STRUCTURES OF BETA PEPTIDE AND ITS CONSTITUENT FRAGMENTS - RELATION TO AMYLOID DEPOSITION

The secondary structures in solution of the synthetic, naturally occurring, amyloid beta-peptides, residues 1 to 42 [beta(1-42)] and beta(1-39), and related fragments, beta(1-28) and beta(29-42), have been studied by circular dichroism and two-dimensional nuclear magnetic resonance spectroscopy. In patients with Alzheimer's disease, extracellular amyloid plaque core is primarily composed of beta(1-42), whereas cerebrovascular amyloid contains the more soluble beta(1-39). In aqueous trifluoroethanol solution, the beta(1-28), beta(1-39), and beta(1-42) peptides adopt monomeric alpha-helical structures at both low and high pH, whereas at intermediate pH (4 to 7) an oligomeric beta-structure (the probable structure in plaques) predominates. Thus, beta-peptide is not by itself an insoluble protein (as originally thought), and localized or normal age-related alterations of pH may be necessary for the self-assembly and deposition of beta-peptide. The hydrophobic carboxyl-terminal segment, beta(29-42), exists exclusively as an oligomeric beta-sheet in solution, regardless of differences in solvent, pH, or temperature, suggesting that this segment directs the folding of the complete beta(1-42) peptide to produce the beta-pleated sheet found in amyloid plaques.