Decoding tau acetylation in Alzheimer’s disease and tauopathies: from site-specific mechanisms to therapeutic horizons

Abstract

Tau acetylation has been recognized as a pivotal post-translationalmodification associated with the pathogenesis of Alzheimer’sdisease (AD) and other tauopathies. This review offers adetailed synthesis of the current understanding of site-specifictau acetylation, its regulatory enzymes, and its profound impactson tau biology. Acetylation influences tau degradation, aggregation,propagation, and microtubule-binding properties in aresidue-specific manner, often in conjunction with other modificationssuch as phosphorylation and ubiquitination. Furthermore,this review emphasizes emerging therapeutic strategiestargeting tau acetylation, including small-molecule inhibitorsof p300/CBP and monoclonal antibodies against acetylated tauepitopes. While several of these approaches are currently undergoingclinical trials, many acetylation sites are still inadequatelycharacterized, emphasizing the need for additionalmechanistic studies. An enhanced understanding of tau acetylationwill be vital for devising targeted therapies to halt or reversethe progression of tau-mediated neurodegeneration.