SOLUTION CONFORMATIONS AND AGGREGATIONAL PROPERTIES OF SYNTHETIC AMYLOID BETA-PEPTIDES OF ALZHEIMERS-DISEASE - ANALYSIS OF CIRCULAR-DICHROISM SPECTRA

The A4 or β-peptide (39 to 43 amino acid residues) is the principal proteinaceous component of amyloid deposits in Alzheimer's disease. Using circular dichroism (c.d.), we have studied the secondary structures and aggregational properties in solution of 4 synthetic amyloid β-peptides: β-(1-28), β-(1-39), β-(1-42) and β-(29-42). The natural components of cerebrovascular deposits and extracellular amyloid plaques are β-(1-39) and β-(1-42), while β-(1-28) and β-(29-42) are unnatural fragments. The β-(1-28), β-(1-39) and β-(1-42) peptides adopt mixtures of β-sheet, α-helix and random coil structures, with the relative proportions of each secondary structure being strongly dependent upon the solution conditions. In aqueous solution, β-sheet structure is favored for the β-(1-39) and β-(1-42) peptides, while in aqueous solution containing trifluoroethanol (TFE) or hexafluoroisopropanol (HFIP), α-helical structure is favored for all 3 peptides. The α-helical structure unfolds with increasing temperature and is favored at pH 1 to 4 and pH 7 to 10; the β-sheet conformation is temperature insensitive and is favored at pH 4 to 7. Peptide concentration studies showed that the β-sheet conformation is oligomeric (intermolecular), whereas the α-helical conformation is monomeric (intramolecular). The rate of aggregation to the oligomeric β-sheet structure (α-helix → random coil → β-sheet) is also dependent upon the solution conditions such as the pH and peptide concentration; maximum β-sheet formation occurs at pH 5.4. These results suggest that β-peptide is not an intrinsically insoluble peptide. Thus, solution abnormalities, together with localized high peptide concentrations, which may occur in Alzheimer's disease, may contribute to the formation of amyloid plaques. The hydrophobic β-(29-42) peptide adopts exclusively an intermolecular β-sheet conformation in aqueous solution despite changes in temperature or pH. Therefore, this segment may be the first region of the β-peptide to aggregate and may direct the folding of the complete β-peptide to produce the β-pleated sheet structure found in amyloid deposits. Differences between the solution conformations of the β-(1-39) and β-(1-42) peptides suggests that the last 3 C-terminal amino acids are crucial to amyloid deposition. © 1992.