PIP₂ Phospholipid-Induced Aggregation of Tau Filaments Probed by Tip-Enhanced Raman Spectroscopy

The morphology and secondary structure of peptide fibers formed by aggregation of tubulin-associated unit (Tau) fragments (K18), in the presence of the inner cytoplasmic membrane phosphatidylinositol component (PIP₂ ) or heparin sodium (HS) as cofactors, are determined with nanoscale (<10 nm) spatial resolution. By means of tip-enhanced Raman spectroscopy (TERS), the inclusion of PIP₂ lipids in fibers is determined based on the observation of specific C=O ester vibration modes. Moreover, analysis of amide I and amide III bands suggests that the parallel β-sheet secondary structure content is lower and the random coil content is higher for fibers grown from the PIP₂ cofactor instead of HS. These observations highlight the occurrence of some local structural differences between these fibers. This study constitutes the first nanoscale structural characterization of Tau/phospholipid aggregates, which are implicated in deleterious mechanisms on neural membranes in Alzheimer's disease.