Probing molecular structure of neurotoxic amyloid Abeta oligomers

Soluble small oligomers of Abeta(1-42) peptide are neurotoxic and represent early biomarkers of AD for their potential role in diffusing toxic species before the late aggregation process occurs. Probing molecular structure of such toxic oligomers is of utmost importance to understand the mechanism by which the early events of neurodegeneration trigger the irreversible neuron death. So far, the disordered nature of Abeta peptide has made any proposal for a structural model for oligomers extremely difficult and many empirical experiments still result controversial. A synergistic combined approach of Raman spectroscopies and extended molecular models is herein adopted to inspect structures and sub-molecular features of the conformation of toxic globular oligomers differentiating them from the non-toxic species. Specifically, UV and visible Raman provide the average structural characterization with extent of secondary motifs and surface localization of aromatic amino acids in the toxic oligomers. On parallel, Raman assisted by localized plasmon resonance at the hot spots of intertwined silver nanowires is exploited to analyse structural features present on the surface of Abeta oligomers that appear critical in driving molecular interactions for neurodegeneration. Our investigation enabled to discriminate among different species of toxic and non-toxic Abeta oligomers, providing characteristic motifs of the aberrant conformers that were unravelled and further confirmed by computational models, while specific amino acid side chains associated with the toxic Abeta species that have so far escaped detection with other techniques were unambiguously identified.