• A novel cell-based Tau aggregation model was constructed using the K18-ΔK280 mutant, which spontaneously aggregates in SH-SY5Y cells without exogenous seeds.
• The model induces co-aggregation and phosphorylation of endogenous Tau at key epitopes (Ser202/Thr205 and Ser396), mimicking pathological Tau modifications.
• This model avoids the cytotoxicity associated with fibrillar seeds, offering a safer and more reproducible platform for studying Tau pathology and screening therapies.
• The system enables investigation of seeding properties and prion-like propagation, providing a valuable tool for Alzheimer's disease research and drug development.