HDAC11 as a potential therapeutic target for Alzheimer's disease

Alzheimer's disease (AD) is the leading cause of dementia. It is characterized by amyloid and tau pathological hallmarks, accompanied by synaptic dysfunction, neuroinflammation, and progressive neuronal loss. Although amyloid-reducing antibodies have recently expanded the disease-modifying therapeutic options, no disease-modifying small-molecule therapeutics are currently available for AD. Epigenetic regulators, particularly histone deacetylases (HDACs), have attracted increasing attention as potential therapeutic targets. Among them, HDAC2, 3 and 6 are supported by broad AD-related evidence, whereas HDAC11 has emerged as a mechanistically distinct potential target. As the sole class IV HDAC and a relatively brain-enriched but not brain-specific lysine defatty-acylase, HDAC11 connects lipid metabolism, innate immunity, microglial function, neuroinflammation, and AD-associated pathology. We discuss advances in HDAC11 biology and AD-related pathology, position HDAC11 among other established AD-relevant HDAC isoforms, and discuss progress relating to HDAC11-selective inhibitors. We pay particular attention to target druggability, chemical probe development, blood-brain barrier penetration, pharmacokinetics, safety and off-target liabilities, and translational promise. In summary, HDAC11 is an emerging therapeutic target in AD, but future studies are needed for chemical optimization, for pathological validation using other disease models, and to show safety and efficacy in the AD context.