Solution Structures of β Peptide and Its Constituent Fragments: Relation to Amyloid Deposition

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Abstract
The secondary structures in solution of the synthetic, naturally occurring, amyloid β peptides, residues 1 to 42 [β(1-42)] and β(1-39), and related fragments, β(1-28) and β(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 β(1-42), whereas cerebrovascular amyloid contains the more soluble β(1-39). In aqueous trifluoroethanol solution, the β(1-28), β(1-39), and β(1-42) peptides adopt monomeric α-helical structures at both low and high pH, whereas at intermediate pH (4 to 7) an oligomeric β structure (the probable structure in plaques) predominates. Thus, β 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 β peptide. The hydrophobic carboxyl-terminal segment, β(29-42), exists exclusively as an oligomeric β sheet in solution, regardless of differences in solvent, pH, or temperature, suggesting that this segment directs the folding of the complete β(1-42) peptide to produce the β-pleated sheet found in amyloid plaques.

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