Tau-directed approaches currently being tested in clinical trials. In Approach 1–5, toxic tau gain of function is targeted by removal or modulation of toxic tau species. In Approach 1, anti-sense oligonucleotides (ASOs) are directed against mRNA from the MAPT gene, thereby reducing translation and decreasing tau gene expression. In Approach 2, healthy post-translational modification (PTM) pathways are supported by blocking hyperphosphorylation by kinases, inhibiting removal of O-GlcNAc, and preventing tau acetylation. In Approach 3, toxic tau aggregates are prevented from forming and existing tau aggregates are disrupted by autophagy. In Approach 4 and 5, antibodies are used to clear or sequester pathologic tau species, preventing cell to cell transmission. In contrast to the prior approaches, in Approach 6 tau loss of function is addressed by restoring microtubule stabilization.
