The Mechanism of GABA in Attenuating Neuroinflammation in Alzheimer’s Disease: CP/CEBPα/miR-34a-Mediated Suppression of HDAC2/3 in Astrocytes

As a widely available dietary supplement, γ-Aminobutyric acid (GABA) exhibits potential for early intervention against Alzheimer's disease (AD). This study demonstrates that GABA alleviates AD neuroinflammation, and its suppression of astrocytic pro-inflammatory cytokine expression through histone deacetylase (HDAC2/3) inhibition contributes to this effect. Here, in both the cerebral cortex of AD mice and Aβ-exposed U251 cells, pro-inflammatory cytokines and HDAC2/3 expression levels were elevated, whereas the levels of creatine phosphate (CP), CCAAT/enhancer-binding protein α (CEBPα) and microRNA34a (miR-34a) were decreased. GABA treatment counteracted these alterations. Silencing HDAC2 or HDAC3 suppressed pro-inflammatory cytokines. Transfection with miR-34a mimics suppressed pro-inflammatory cytokines and HDAC2/3 expression in U251 cells, while miR-34a inhibitors had the opposite effect. A luciferase reporter assay confirmed HDAC2 as a direct miR-34a target via 3'UTR binding. Knockdown of CEBPα suppressed miR-34a expression, thereby elevating HDAC2/3 and pro-inflammatory cytokine expression in U251 cells. In CP-treated U251 cells, CEBPα and miR-34a expression was elevated, while pro-inflammatory cytokine and HDAC2/3 expression was down-regulated. In conclusion, GABA alleviates neuroinflammation in AD model mice. This effect may be partially attributed to its suppression of astrocyte-derived pro-inflammatory cytokine expression via HDAC2/3 inhibition. The CP/CEBPα/miR-34a pathway mediates the inhibitory effect of GABA on HDAC2/3 expression.