HDAC3's Pathogenic Role in Alzheimer's Disease: Established Links, Unresolved Questions, and Translational Roadmap Defined

The progressive neurodegenerative disorder Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles, leading to synaptic dysfunction and neuroinflammation. Despite extensive research, effective disease-modifying therapies remain elusive, partly due to an incomplete understanding of core pathogenic mechanisms. Histone deacetylase 3 (HDAC3) has emerged as a potential player, but its precise involvement and therapeutic utility in AD pathology, including its impact on Aβ and Tau dynamics, are not fully established.

This mini-review critically synthesized existing literature on the role of Histone deacetylase 3 (HDAC3) in Alzheimer's disease (AD). The authors systematically examined evidence linking HDAC3 to key AD pathologies, specifically amyloid-β (Aβ) accumulation, Tau pathology, neuroinflammation, and synaptic dysfunction. The review focused on identifying established findings, highlighting areas of uncertainty, and outlining crucial steps needed for the clinical translation of HDAC3-targeted therapies. It also discussed major limitations in the current research landscape, including methodological inconsistencies and translational hurdles.

The review established that HDAC3 is increasingly implicated in Alzheimer's disease (AD), with evidence linking its activity to multiple pathogenic hallmarks. Specifically, HDAC3 has been associated with amyloid-β (Aβ) accumulation, Tau pathology, neuroinflammation, and synaptic dysfunction. However, the authors identified several critical limitations in the field. These include weak causal evidence for HDAC3's direct role in AD progression, inconsistent cell type-specific findings across various studies, and insufficient validation in human brain tissue. A significant gap is the lack of proof that HDAC3 acts as a central mechanistic node across the diverse AD-related pathways. > Translational challenges are also substantial, encompassing issues like poor inhibitor selectivity, uncertain brain penetrance of current compounds, and potential safety concerns, alongside an absence of standardized preclinical benchmarks. The review concludes that future progress necessitates robust human evidence, targeted cell type-specific causal studies, integrated mechanistic models, and more rigorous pharmacological validation to solidify HDAC3's therapeutic potential.