Abstract
Amyloid β peptide (Aβ) is causatively associated with Alzheimer's disease (AD), and N-terminally truncated and pyroglutamylated Aβ peptides (AβpE) exert hypertoxic effect by an unknown mechanism. Recent evidence has identified the prefibrillar oligomers of Aβ, not the fibrils, as the prevalent cytotoxic species. Structural characterization of Aβ and AβpE oligomers is therefore important for better understanding of their toxic effect. Here we have used isotope-edited Fourier transform infrared (FTIR) spectroscopy to identify the conformational changes in Aβ(1-42) and AβpE(3-42) upon aggregation, individually and in 1 : 1 molar combination. During the first two hours of exposure to aqueous buffer, the peptides undergo transition from mostly α-helical to mostly β-sheet structure. Data on peptides (13)C,(15)N-labeled at K(16)L(17)V(18) or V(36)G(37)G(38)V(39) allowed construction of structural models for the monomer and early oligomers. The peptide monomer comprises a β-hairpin that involves residues upstream of the K(16)L(17)V(18) sequence and an N-terminal α-helix. The oligomers form by non-H-bonding interactions between the β-strands of neighboring β-hairpins, in lateral or staggered manner, with the strands running parallel or antiparallel. Relative α-helical and β-sheet propensities of Aβ(1-42) and AβpE(3-42) depend on the ionic strength of the buffer, emphasizing the importance of ionic interactions in Aβ peptide structure and aggregation. It is inferred that N-terminal modification of AβpE(3-42) affects the helix stability and thereby modulates β-sheet oligomer formation. The data thus provide new insight into the molecular mechanism of Aβ oligomerization by emphasizing the role of the N-terminal transient α-helical structure and by identifying structural constraints for molecular organization of the oligomers.