HDACs in the Brain: From Chromatin Remodeling to Neurodegenerative Disease

Abstract

Histone deacetylases (HDACs) are key epigenetic regulators that influence chromatin remodeling, gene expression, and cellular plasticity in the central nervous system (CNS). This review provides a comprehensive overview of the classification and functional diversity of HDACs, with particular emphasis on their roles in neural progenitor cells, mature neurons, and glial populations. In neural stem and progenitor cells, HDACs modulate neurogenesis, fate specification, and lineage commitment. In differentiated neurons, HDACs govern synaptic plasticity, memory formation, and survival. In glial cells, including astrocytes and microglia, HDACs orchestrate inflammatory responses, redox balance, and metabolic adaptations. We further examine the dysregulation of HDAC expression and activity in major neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Evidence from human post-mortem brain studies reveals region- and isoform-specific alterations in HDAC expression, which are closely associated with cognitive decline, mitochondrial dysfunction, and neuroinflammation. Preclinical studies support the use of HDAC inhibitors (HDACi) as neuroprotective agents, capable of restoring acetylation homeostasis, reducing neuroinflammation, and improving neuronal function. Given the relevance of HDACi, we summarize current clinical studies assessing the safety of these compounds in the context of tumor biology, as well as their potential future applications in neurodegenerative diseases. Together, this review underscores the dual significance of HDACs as biomarkers and therapeutic targets in the context of CNS disorders.

Keywords: HDAC inhibitors; epigenetic regulation; glial cells; histone deacetylases; neurodegenerative diseases; neurogenesis; neuroinflammation; synaptic plasticity.

Figure 1

Expression patterns and major functions of HDACs in CNS cell types. This schematic summarizes the predominant HDAC isoforms expressed in neural progenitor cells (NPCs), neurons, astrocytes, and microglia, along with their primary functions. HDACs regulate essential processes such as proliferation, differentiation, synaptic function, gliogenesis, inflammation, and neuroprotection. Their expression is cell-type-specific and dynamically regulated throughout development and in response to injury or disease.

Figure 2

LASSBio-1911 modulates HDAC activity and astrocyte reactivity to reverse synaptic and memory deficits in an AD model. Astrocyte exposure to Aβ oligomers (AβO) induces increased HDAC activity and a pro-inflammatory reactive phenotype in an AD animal model. This leads to reduced histone acetylation, synapse loss, and memory impairment. Treatment with the synthetic compound LASSBio-1911 attenuates astrocyte reactivity, decreases HDAC activity, restores histone acetylation levels, and rescues both synaptic integrity and cognitive function. The schematic summarizes the pathological cascade and therapeutic reversal observed in vivo.

Figure 3

Chemical structures of representative HDACi with different BBB penetration profiles. Valproic acid, a short-chain fatty acid, generally exhibits good BBB permeability but limited isoform selectivity. Romidepsin, a cyclic depsipeptide, is highly potent yet shows poor passive BBB penetration. Entinostat, an aromatic anilide derivative, presents moderate BBB permeability and class I HDAC selectivity. LASSBio-1911 is a synthetic multifunctional compound with HDAC inhibitory and neuroprotective properties; preclinical studies indicate that it inhibits HDAC activity in vivo.