CW-Tau fights proteinopathy by improving autophagy and diminishing Tau seeding activity

CW-Tau, a novel MAPT transcript variant generated by intron 12 retention, has been identified. Compared with classical Tau isoforms, this isoform has greater microtubule-binding properties, a reduced aggregation propensity, and faster turnover. Notably, CW-Tau RNA and protein levels are decreased in Alzheimer’s disease (AD) brains. To investigate its molecular interactions, we performed affinity chromatography using the W-Tau peptide, which is encoded by intron 12, and identified key binding partners involved in microtubule dynamics, vesicle trafficking, and autophagy. The W-Tau peptide interacts with tubulin, suggesting the presence of an additional microtubule-binding domain, and binds lactate dehydrogenase, preventing its aggregation. Furthermore, the W-Tau peptide is associated with vesicle trafficking regulators, including Rab proteins and Rab-GDP dissociation inhibitors, as well as autophagy-related proteins such as MAP1BLC1 and PARK7. Unlike classical Tau isoforms, which disrupt these pathways, CW-Tau functionally preserves vesicle trafficking and autophagic flux. Importantly, while classical Tau isoforms promote pathological transmission of Tau either nakedly or via exosome-mediated export, CW-Tau counteracts this process, demonstrating potent antiseeding activity. By preventing Tau aggregation and propagation, CW-Tau may play a protective role against proteinopathy-related neurodegeneration. These findings suggest that CW-Tau is a promising therapeutic tool for AD, offering potential strategies to restore cellular proteostasis and inhibit Tau pathology.