Acer truncatum Bunge seed oil ameliorates cuprizone-induced cognitive decline and brain white matter impairment by improving sphingomyelin metabolism and neuroinflammation via activation of the TREM2 signaling pathway

seed oil (ATSO) against cuprizone-induced white matter injury and cognitive decline. A comprehensive analysis integrating techniques from animal behavior, histopathology, immunology and network pharmacology was performed. The results showed that ATSO ameliorated the cuprizone-induced cognitive impairment, corpus callosum demyelination, synaptic loss, and inflammatory activation of microglia and astrocytes. Mechanistically, ATSO reversed the cuprizone-induced demyelination by enhancing sphingomyelin metabolism and activating the TREM2-APOE signaling pathway. The network pharmacology study revealed that the cognitive protection, sphingomyelin metabolism regulation, and anti-inflammatory effects of ATSO were mediated by its unsaturated fatty acid components. Validated by experimental data, the core targets of ATSO were found to be centered on the TREM2 network. In conclusion, ATSO ameliorates cuprizone-induced cognitive impairment and brain white matter lesions by improving sphingomyelin metabolism and alleviating neuroinflammation through activation of the TREM2 signaling pathway.