Chemical Imaging of RNA-Tau Amyloid Fibrils at the Nanoscale Using Tip-Enhanced Raman Spectroscopy

Area of Science:

• Neuroscience
• Biophysics
• Biochemistry

Background:

• Tau protein aggregation into amyloid deposits is a hallmark of neurodegenerative diseases.
• Cofactors like heparin, lipids, and RNA are known to induce tau aggregation in vitro.
• The precise mechanisms of cofactor-tau interactions remain poorly understood.

Purpose of the Study:

• To investigate the spatial distribution and interaction of polyadenosine (polyA) with tau protein in single fibrils.
• To elucidate the role of RNA cofactors in the formation of toxic tau aggregates.
• To demonstrate the utility of tip-enhanced Raman spectroscopy (TERS) for analyzing individual tau fibrils.

Main Methods:

• Utilized tip-enhanced Raman spectroscopy (TERS) for nanoscale visualization (<10-20 nm).
• Analyzed the distribution of adenine, protein secondary structure (β-sheet core, random coil), and specific amino acids (arginine, lysine, histidine).
• Employed reference unenhanced and surface-enhanced Raman spectra for spectral interpretation.

Main Results:

• Demonstrated incorporation of the polyA cofactor within the tau fibril structure.
• Showed polyA is located superficially to the β-sheet core but within the random-coiled outer layer.
• Confirmed colocalization of positively charged amino acids (arginine, lysine, histidine) with negatively charged polyA.

Conclusions:

• PolyA cofactor is integrated into tau fibrils, interacting with specific amino acids.
• TERS provides nanoscale insights into cofactor localization and interaction within individual tau fibrils.
• Understanding these interactions is crucial for comprehending tau-mediated neurodegeneration and developing therapeutic strategies.