Amyloid β-peptides 1–40 and 1–42 form oligomers with mixed β-sheets

Abstract

Two main amyloid-β peptides of different length (Aβ₄₀ and Aβ₄₂) are involved in Alzheimer's disease. Their relative abundance is decisive for the severity of the disease and mixed oligomers may contribute to the toxic species. However, little is know about the extent of mixing. To study whether Aβ₄₀ and Aβ₄₂ co-aggregate, we used Fourier transform infrared spectroscopy in combination with ¹³C-labeling and spectrum calculation and focused on the amide I vibration, which is sensitive to backbone structure. Mixtures of monomeric labeled Aβ₄₀ and unlabeled Aβ₄₂ (and vice versa) were co-incubated for ∼20 min and their infrared spectrum recorded. The position of the main ¹³C-amide I′ band shifted to higher wavenumbers with increasing admixture of ¹²C-peptide due to the presence of ¹²C-amides in the vicinity of ¹³C-amides. The results indicate that Aβ₄₀ and Aβ₄₂ form mixed oligomers with a largely random distribution of Aβ₄₀ and Aβ₄₂ strands in their β-sheets. The structures of the mixed oligomers are intermediate between those of the pure oligomers. There is no indication that one of the peptides forces the backbone structure of its oligomers on the other peptide when they are mixed as monomers. We also demonstrate that isotope-edited infrared spectroscopy can distinguish aggregation modulators that integrate into the backbone structure of their interaction partner from those that do not. As an example for the latter case, the pro-inflammatory calcium binding protein S100A9 is shown not to incorporate into the β-sheets of Aβ₄₂.