RawData_Shapeshifter W-tau peptide inhibits tau aggregation and disintegrate paired helical filaments

Tauopathies comprise a range of neurodegenerative conditions characterized by an aberrant accumulation of tau protein clumps in the brain. These aggregates are formed by different tau splicing isoforms. Here, we analyzed the role of the specific intron-derived peptide called W-Tau peptide on the polymerization-depolymerization of tau filaments. This peptide originates from a new isoform of the tau protein, named W-Tau, which is formed due to the retention of intron 12. AlphaFold3 (AF3)-based in silico investigations suggested that W-Tau peptide interacts with tau monomers. Our in vitro experiments confirmed these predictions and showed that W-Tau peptide inhibited tau aggregation. In addition, W-Tau peptide successfully disrupted pre-existing paired helical filaments (PHFs) isolated from postmortem brain samples of patients with Alzheimer’s disease, thereby supporting its potential therapeutic value. The effectiveness of the W-Tau peptide was demonstrated in cell cultures by a noteworthy decrease in tau aggregation observed after co-transfection, of W-Tau peptide and PHFs’ seeds, as demonstrated by analysis involving a fluorescence resonance energy transfer (FRET) cell biosensor. The W-Tau peptide breaks PHFs by selectively attaching to their ends, causing the structures to unwind and convert into circle-like formations. Considering the potential neuroprotective effects against tauopathies, the W-Tau isoform and its peptide are interesting candidates for future therapeutic interventions