Chunk #26 — Therapeutic approaches to toxic tau gain of function — Approach 2: modulate tau post-translational modification (PTM) — Acetylation inhibitors
As described above, abnormal acetylation at lysine residues can prevent physiologic clearance of tau, and K174 was identified as an important acetylation site critical for tau homeostasis. In PS19 transgenic mice that express human tau gene with the P301S mutation, treatment with salsalate, a small molecule anti-inflammatory agent that precedes the FDA approval process, was found to reduce tau acetylation at K174, decrease tau aggregations, and rescue memory deficits. [71] These preclinical data led to two Phase 1/2 trials for salsalate, and the first trial (SAL-AD) will look at safety and pharmacokinetics after 12 months of treatment in 40 mild to moderate AD patients (NCT03277573). The second trial screened for treatment effect in 10 patients with PSP, but no evidence of efficacy was found after treatment for 6 months [72].
