Pan-HDAC Inhibitors Promote Tau Aggregation by Increasing the Level of Acetylated Tau

Histone acetylation-mediated epigenetic remodeling has emerged as a promising therapeutic approach for Alzheimer’s disease (AD). Notably, histone deacetylase (HDAC) inhibitors such as M344 and SAHA have been identified as potential drug candidates, demonstrating the ability to enhance cognitive function in AD mouse models. However, despite their therapeutic potential, most HDAC inhibitors exhibit poor selectivity, which may lead to undesirable side effects. Here, we demonstrate that tau is a cytosolic substrate of HDAC, and treatment with HDAC inhibitors—including Scriptaid, M344, BML-281, and SAHA—leads to increased acetylated tau levels, ultimately promoting tau pathology.