HDAC1 K438 Lactylation is Associated with NF-κB-related Microglial Inflammatory Activation in Alzheimer’s Disease
Year: 2026
Type: preprint
Abstract: Alzheimer’s disease (AD) is characterized by persistent microglial activation, yet how metabolic stress contributes to inflammatory reprogramming remains unclear. This study investigated the role of histone deacetylase 1 (HDAC1) lactylation in microglial inflammation. HDAC1 and global protein lactylation were examined in human AD prefrontal cortex and 5×FAD mice, alongside human single-nucleus and spatial transcriptomic analyses. Proteomic and lactylomic profiling of BV2 microglia exposed to hypoxia and lipopolysaccharide (LPS-Hy) was used to characterize inflammatory reprogramming and identify candidate HDAC1 lactylation sites, followed by molecular docking and mutagenesis. HDAC1 lactylation and global protein lactylation signals were elevated in IBA1-positive microglia in human AD tissue and 5×FAD mice and associated with activation markers. Transcriptomic analyses revealed no corresponding increase in HDAC1 mRNA in AD microglia, implicating post-translational modification in HDAC1-associated inflammatory regulation. Lactylomic profiling identified K438 as a major HDAC1 lactylation site, while molecular docking suggested structural compatibility between lactate and the HDAC1 catalytic pocket. Wild-type HDAC1 enhanced LPS-Hy-induced Il1b and Nos2 expression, whereas the K438R mutant abolished detectable HDAC1 lactylation and lost this enhancing effect, accompanied by altered total p65 abundance. Cross-dataset integration identified a conserved immune–metabolic microglial module across human AD, Aβ-positive microglia, and LPS-Hy-treated BV2 cells, with HDAC1 as a highly connected network hub. Together, these findings support a role for HDAC1 K438 lactylation in regulating microglial inflammatory responses under metabolic and inflammatory stress, highlighting a potential non-histone post-translational mechanism linking cellular stress to immune-metabolic reprogramming and a candidate target for further investigation in AD.
Source: Research Square
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7225632287