A number of pathogenic MAPT mutations associated with FTDP-17 can alter tau’s binding kinetics, increasing the levels of unbound tau and therefore its propensity to misfold and aggregate. Although it has been previously hypothesized that the disassociation of tau from microtubules, reflective of its loss of function, could potentially play a role in the pathogenesis of the disease, the current view in the field is that the deleterious effects of tau pathology are due to toxic gain of function of tau. This is consistent with the observation that tau knockout mice are essentially healthy. Furthermore, Tau reduction has been found to be not only safe but also neuroprotective in mouse models of excitotoxicity and seizures. [12,13] Thus, it is clear that tau toxicity plays a critical role in the pathogenesis of tauopathies, however the molecular mechanisms of this toxicity remains unclear. There is limited understanding of what forms of tau confer its toxicity and how tau aggregates interfere with cellular function leading to neurodegeneration. The main reason for this gap in our knowledge comes from the complexity of tau proteins
