Shapeshifter W-Tau Peptide Inhibits Tau Aggregation and Disintegrates Paired Helical Filaments

Tauopathies comprise a range of neurodegenerative conditions characterized by the aberrant accumulation of tau protein clumps in the brain. These aggregates are formed by different tau splicing isoforms. Here, we analyzed the role of a specific intron-derived peptide called the 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 <i>in silico</i> investigations suggested that the W-Tau peptide interacts with tau monomers. Our <i>in vitro</i> experiments confirmed these predictions and showed that the W-Tau peptide inhibited tau aggregation. In addition, the W-Tau peptide disrupted preexisting 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 by the decrease in tau aggregation observed after cotransfection of the W-Tau peptide and PHF 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.