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

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Abstract
Summary Paragraph: Tau misfolding and aggregation are central to cognitive decline in Alzheimer’s disease and related neurodegenerative disorders 1–3 . Although soluble tau oligomers are implicated as primary toxic species 4–6 , 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 Alzheimer’s disease brains uncovers enrichment of antiparallel β-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.
Funding Information
  • National Institutes of Health (R35GM136223)
  • National Institutes of Health (R01AI141439)
  • National Institutes of Health (R33CA261726)
  • Boston University Ignition Award (N/A)
  • National Institutes of Health (R35GM156801)
  • National Institute on Aging (NIA), National Institutes of Health (R01AG091577)
  • Cure Alzheimer' s Cardinal Family Scholars Fund (N/A)

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