To generate a robust hiPSC-derived model for tauopathies, we introduced in a footprint-free manner three MAPT mutations (N279K, P301L and E10+16) into hiPSCs and differentiated the cells towards cortical neurons, finding that mutant neurons expressed higher levels of 4R Tau, higher phosphorylation and aggregation of Tau, an increased electrophysiological activity, deficiencies in neurite outgrowth, aberrant sequence of differentiation to cortical neurons, and a significant activation of stress response pathways. This evidence concerns the gene MAPT and tauopathy.