Characterizations of distinct amyloidogenic conformations of the Aβ (1–40) and (1–42) peptides

Abstract

Major constituents of the amyloid plaques found in the brain of Alzheimer’s patients are the 39–43 residue β-amyloid (Aβ) peptides. Extensive in vitro as well as in vivo biochemical studies have shown that the 40- and 42-residue Aβ peptides play major roles in the neurodegenerative pathology of Alzheimer’s disease. Although the two Aβ peptides share common aggregation properties, the 42-residue peptide is more amyloidogenic and more strongly associated with amyloid pathology. Thus, characterizations of the two Aβ peptides are of critical importance in understanding the molecular mechanism of Aβ amyloid formation. In this report, we present combined CD and NMR studies of the monomeric states of the two peptides under both non-amyloidogenic (<5 °C) and amyloid-forming conditions (>5 °C) at physiological pH. Our CD studies of the Aβ peptides showed that initially unfolded Aβ peptides at low temperature (<5 °C) gradually underwent conformational changes to more β-sheet-like monomeric intermediate states at stronger amyloidogenic conditions (higher temperatures). Detailed residue-specific information on the structural transition was obtained by using NMR spectroscopy. Residues in the N-terminal (3–12) and 20–22 regions underwent conformational changes to more extended structures at the stronger amyloidogenic conditions. Almost identical structural transitions of those residues were observed in the two Aβ peptides, suggesting a similar amyloidogenic intermediate for the two peptides. The 42-residue Aβ (1–42) peptide was, however, more significantly structured at the C-terminal region (39–42), which may lead to the different aggregation propensity of the two peptides.