Astragalus polysaccharide ameliorates neuroinflammation in EAE mice by modulating microglial autophagy to reduce lipid droplet accumulation

Multiple sclerosis (MS) is an immune-mediated inflammatory demyelinating disease of the central nervous system. Emerging evidence indicates a close association between lipid metabolism disorders and MS, wherein microglial neuroinflammation driven by aberrant lipid droplet accumulation represents a core pathological mechanism. In this study, we first performed GEO database-based differential gene enrichment analysis related to lipid metabolism and GWAS-based Mendelian randomization analysis, demonstrating that disordered lipid metabolism constitutes a key pathological feature of MS with lipid droplets playing a central role. Based on these findings and our previous work demonstrating the efficacy of APS in alleviating neuroinflammation and neurological deficits in experimental autoimmune encephalomyelitis (EAE) mice, we sought to elucidate its role and mechanism in regulating microglial lipid droplets metabolism and neuroinflammation in the EAE mice and LPS-stimulated BV2 microglia model. Results demonstrated impaired autophagic flux, increased lipid droplets accumulation, and elevated pro-inflammatory cytokine secretion in both EAE mice brain tissue and LPS-stimulated BV2 microglia model. Critically, APS intervention reversed these pathological changes. APS activated microglial autophagic flux, enhanced lipophagy function, cleared accumulated lipid droplets, and consequently suppressed pro-inflammatory factor secretion, thereby alleviating neuroinflammation. In conclusion, APS alleviates MS neuroinflammation partially by enhancing microglial lipophagy, which facilitates the elimination of lipid droplets accumulation. This finding provides a novel therapeutic strategy and lays a theoretical foundation for developing neuroprotective drugs targeting lipophagy.

Astragalus polysaccharides; Autophagy; Lipid droplets; Lipophagy; Microglia; Multiple sclerosis.