IR-AMES uncovers structure and composition of Alzheimer' s tau oligomers

Summary ParagraphTau misfolding and aggregation are central to cognitive decline in Alzheimers disease and related neurodegenerative disorders1-3. Although soluble tau oligomers are implicated as primary toxic species4-6, the structural and compositional determinants of their toxicity remain inaccessible at the single oligomer level. Here we introduce infrared absorbance-modulated evanescent scattering (IR-AMES), a label-free single-molecule spectroscopic imaging approach that photothermally encodes mid-infrared vibrational fingerprints into evanescent scattering from individual biomolecular assemblies under native aqueous conditions. Applying IR-AMES to recombinant human tau resolves random-coil-dominated monomers and captures the emergence of structurally heterogeneous oligomers. Analysis of tau oligomers from postmortem Alzheimers disease brains uncovers enrichment of antiparallel {beta}-sheet structures and RNA components, features that are largely obscured in ensemble-averaged measurements. Using lipid nanodiscs as a defined membrane mimic, we further show that pathological tau oligomers exhibit enhanced interactions with anionic membranes. Together, these findings establish a link between structure and neurotoxicity of tau oligomers, and position IR-AMES as a platform for uncovering structure-function relationships in complex biomolecular assemblies.