Histone Deacetylase Inhibitors Improve Memory Function and Decrease Neuropathology in APP/PS1 Mice

Although histone deacetylase (HDAC) inhibitors have shown therapeutic potential in aging and Alzheimer's disease (AD), direct comparisons of nonselective and selective HDAC inhibitors across aging and AD models are lacking. We compared the effects of the broad-spectrum HDAC inhibitor valproic acid (VPA) and the selective class I HDAC inhibitors entinostat (MS-275) and tacedinaline (CI-994) in 3-, 12-, and 18-month-old wild-type and APP/PS1 mice. Mice received 30 days of treatment, followed by a series of behavioral tests assessing different memory domains. Brain tissue was then analyzed for molecular and pathological changes. Both MS-275 and CI-994 improved recognition memory and short-term working memory in 12- and 18-month-old APP/PS1 mice, whereas only CI-994 restored long-term spatial reference memory. CI-994 increased hippocampal synapse-related gene expression and H3K9 acetylation at their promoters, consistent with improved hippocampus-dependent memory. In contrast, MS-275 enhanced synapse-related gene expression and H3K9 acetylation, in the prefrontal cortex (PFC), corresponding to improvements in recognition and working memory. MS-275 also significantly reduced amyloid plaque burden in the hippocampus and PFC, whereas both MS-275 and CI-994 decreased microglial density in APP/PS1 mice. These findings demonstrate distinct spatial and functional effects of selective HDAC inhibition in AD. CI-994 primarily targets hippocampal synaptic plasticity to improve long-term spatial memory, whereas MS-275 preferentially modulates PFC synaptic function and reduces amyloid pathology, leading to improved recognition and working memory. Together, these results identify region-specific HDAC mechanisms that differentially regulate cognitive function and AD pathology, supporting selective HDAC inhibition as a promising therapeutic strategy for AD.