Nanoscale insights into the structure of tau protein fibrils

Abstract

Tau protein aggregation is a key hallmark of Alzheimer’s disease, making its structural characterization essential for understanding pathological mechanisms and guiding therapeutic strategies. Using tip enhanced Raman spectroscopy (TERS), nanoscale chemical information can be obtained from individual tau aggregates at successive stages of fibril maturation. TERS enabled detection of local secondary structure transitions and clear spectral differentiation between full length tau and the truncated K18 fragment in early aggregation phases. Multivariate data analysis identified vibrational markers of progressive structural ordering, while hyperspectral TERS imaging revealed intrafibrillar heterogeneity resulting from secondary nucleation. Residue specific contributions were also observed, with histidine active at early stages and phenylalanine/tyrosine linked to β sheet stabilization. Nanoscale effects of curcumin as an aggregation inhibitor will also be discussed. Acknowledgments: This research was funded by National Science Centre, Poland, under the SONATA 17 project (Reg. No. UMO-2021/43/D/ST4/02655).