Altogether, the comparison between WT and 2P tau suggests that the behavioral impairments caused by the overexpression of human WT tau are likely to be conferred by increased burden of hyperphosphorylation, rather than by the accumulation of misfolded tau protein. Remarkably, amino acid substitutions that affect the conformation of the microtubule-binding region of 4R0N tau have major effects on the downstream accumulation of hyperphosphorylated tau, and prevent the impairments of motor behavior observed in this mouse model.