Acetylation: A new key to unlock tau's role in neurodegeneration

The identification of tau protein as a major constituent of neurofibrillary tangles spurred considerable effort devoted to identifying and validating pathways through which therapeutics may alleviate tau burden in Alzheimer's disease and related tauopathies, including chronic traumatic encephalopathy associated with sport- and military-related injuries. Most tau-based therapeutic strategies have previously focused on modulating tau phosphorylation, given that tau species present within neurofibrillary tangles are hyperphosphorylated on a number of different residues. However, the recent discovery that tau is modified by acetylation necessitates additional research to provide greater mechanistic insight into the spectrum of physiological consequences of tau acetylation, which may hold promise as a novel therapeutic target. In this review, we discuss recent findings evaluating tau acetylation in the context of previously accepted notions regarding tau biology and pathophysiology. We also examine the evidence demonstrating the neuroprotective and beneficial consequences of inhibiting histone deacetylase (HDAC)6, a tau deacetylase, including its effect on microtubule stabilization. We also discuss the rationale for pharmacologically modulating HDAC6 in tau-based pathologies as a novel therapeutic strategy.