Targeting Histone Deacetylase 2 in Alzheimer's Disease: From Molecular Insights to Epigenetic Therapeutic Opportunities.

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to cognitive impairment, memory loss, and nerve cell dysfunction. Despite substantial research efforts, effective AD therapies remain limited. Histone deacetylase 2 (HDAC2) is a principal epigenetic regulator that is essential for controlling gene expression and neuronal connectivity. Recently, HDAC2 has attracted significant attention as a potential therapeutic target in AD owing to its involvement in key disease hallmarks, including neuroinflammation, Aβ accumulation, and abnormal tau phosphorylation. We have outlined and discussed the molecular insights into HDAC2 in AD and its recently emerged inhibitors. Inhibiting HDAC2 has demonstrated potential in lowering neuroinflammatory signalling and reestablishing synaptic and neuroprotective gene expression patterns in preclinical AD models. Current preclinical evidence indicates that HDAC2 may play a significant role in AD development and may represent a target for therapeutic intervention. Recent progress in HDAC2 inhibitor development offers a rationale for this approach, although further mechanistic and clinical investigations are required. Resolving the precise roles of HDAC2 dysregulation in AD and determining the utility of combination strategies remain important priorities. Whether HDAC2-targeted inhibitors can yield disease-modifying benefits in AD remains to be demonstrated in clinical studies.