Abstract: Tauopathies, including Alzheimer’s disease and frontotemporal dementia, are neurodegenerative disorders characterized by the intracellular accumulation of Tau protein aggregates. These aggregates propagate between interconnected neurons through prion-like mechanisms, emphasizing the pivotal role of Tau spreading in disease progression. The Tau protein harbors amyloidogenic motifs, such as VQIVYK within its microtubule-binding domain, which are critical for Tau aggregation and seeding. Despite the significance of these processes, therapeutic strategies targeting Tau pathology remain limited. In this study, we employed CRISPR/Cas9 gene-editing technology to generate isogenic induced pluripotent stem cell (iPSC) lines with MAPT mutations (N296Δ, P301L, P301S, and P332S) located within or near the R2R3 interface. To model Tau pathology, these isogenic iPSCs were differentiated into neuronal cells (hiPSC-iN) using an NGN2-based protocol. By week six, these neurons exhibited maturation and stress-induced Tau aggregation following thapsigargin treatment. Future investigations will evaluate whether MAPT mutations exacerbate Tau aggregation in hiPSC-iN and assess the efficacy of VQIVYK inhibitors in mitigating Tau seed formation and aggregation. This study highlights the utility of isogenic iPSC models and hiPSC-derived neurons as robust platforms for elucidating the molecular mechanisms underlying Tau pathology and for advancing therapeutic approaches targeting Tau aggregation and propagation.
