*3.2.3. Acetylation*

Tau lysine residues could be acetylated by certain endogenous acetyltransferase, and such modulations were first demonstrated by p300 and Creb-binding protein (CBP) [138, 139]. Importantly, the insoluble tau protein fraction isolated from postmortem brains of the AD patients could be recognized by an anti-acetylated tau antibody [138]. Since then, tau acetylation studies start to emerge, and up to date, four tau acetylation sites, K174, K274, K280, and K281, have been confirmed in pathological conditions [140]. Acetylation of K280 and K281 reduced tau binding affinity to microtubules in vivo and facilitated tau aggregation in vitro [140, 141]. Moreover, acetylation of K280 exacerbated tau toxicity in a *Drosophila* model, and acetylation of K174 worsened neurodegeneration and behavior defects in PS19 mice [142, 143]. An overall tau acetylation effect is likely to aggravate tau toxicity. A study showed the administration of salsalate, a drug that could inhibit p300, ameliorated the tau pathology and memory defects in PS19 mice [143]. Interestingly, a recent study reported acetylation of K321 could impede S324 phosphorylation, a frequent modification in postmortem AD brains. This observation leads to an intriguing prospect that some switches from acetylation to phosphorylation might affect disease progression [144]. Altogether, these studies bring up questions including to what extent tau acetylation could affect tau toxicity and whether there are interactions between tau acetylation and other posttranslational modifications.
