Retinoic acid as a metabolic modulator in Alzheimer's disease: activating oxidative phosphorylation to counteract inflammation in microglia

Alzheimer’s disease (AD), the most common neurodegenerative disorder, is marked by progressive cognitive decline and chronic neuroinflammation, primarily driven by dysfunctional microglia. In AD pathology, activated microglia undergo a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis, exacerbating inflammation and reducing their neuroprotective functions. Therapeutic strategies capable of reprogramming this metabolic phenotype are of growing interest. Based on the hypothesis that epigenetic compounds can reverse this metabolic switch, we screened a library of nearly 200 drugs on BV2 microglial cells using a transcriptomic platform. Retinoic acid (RA) emerged as the most potent inducer of OXPHOS-associated transcriptional programs. Transcriptomic analyses, including PCA, GSVA, and GSEA, confirmed the robust upregulation of mitochondrial pathways in RA-treated cells and revealed a concomitant downregulation of inflammation-associated genes. Functional validation using Seahorse XF technology revealed a dose- and time-dependent increase in mitochondrial respiration following RA treatment, with significant enhancements in basal respiration, ATP production, maximal respiration, and spare respiratory capacity. These findings indicate that RA drives a metabolic reprogramming toward OXPHOS and attenuates inflammatory activity in microglia. This study highlights the potential of RA as a metabolic modulator capable of restoring microglial homeostasis and presents a promising therapeutic strategy to mitigate neuroinflammation in Alzheimer’s disease.