Six main approaches are being tested, including reducing MAPT gene expression, modulating post-translational modification, preventing tau aggregation, immune neutralization or clearance of different tau species via either active or passive strategies, and stabilizing microtubules (Fig. 1). The overarching hypotheses being tested through these studies are 1) the predominant hypothesis that tauopathies are caused by a toxic gain of tau function (post-translational modification, misfolding, aggregation and or altered expression) leading to neuronal dysfunction and death, [12] which would require prevention, disruption and/or clearance; or 2) neurodegeneration is in part a consequence of loss of normal tau function, e.g. binding to and stabilizing microtubules or other cellular functions, which would require agents to supplement this function [30]. Importantly, these mechanisms of tau toxicity are not mutually exclusive, e.g. toxic tau gain of function could interfere with physiological tau function leading to secondary loss of function.
