After transcription and alternative splicing, tau undergoes extensive post-translational modification by processes such as phosphorylation, O-GlcNAcylation, acetylation, and proteolytic cleavage by caspases and other proteases [25]. PTM regulates tau’s diverse functions, and phosphorylated tau (pTau) plays a crucial role in normal physiology, including tau binding to microtubules [26]. In contrast, abnormal phosphorylation patterns (e.g. hyperphosphorylation) are associated with pathologic tau aggregation, primarily in AD [27]. It has been proposed that physiologic clearance of tau is also partially dependent on PTM, typically via ubiquitination and routing of tau to the proteasome. Acetylation of tau at lysine residues prevents ubiquitination and clearance, allowing hyperphosphorylation and tau aggregation [28]. In human AD brains, increased acetylation has been demonstrated in tau aggregates, raising the possibility that an acetylation inhibitor may increase the physiologic clearance of tau and prevent tau aggregation [29].
