Integrated metabolomics and transcriptomics reveal the neuroprotective effect of nervonic acid on LPS-induced AD model mice

Nervonic acid (NA) is one of the long-chain fatty acids with significant biological activity that has been widely studied in recent years. It is believed that NA may play a crucial role in the recovery of human cognitive disorders. Although many literatures have shown that NA has some neuroprotective effect in experimental animal models, the detailed neuroprotective mechanism of NA is still poorly understood. In this study, we applied behavioral, transcriptomic and metabolomic approaches to analyze the neuroprotective effect of NA and its molecular mechanism in AD (Alzheimer’s disease) model mice. We demonstrated that NA improved motor skills and learning and memory abilities of mice at the behavioral level. To further understand the specific pathways involved in this protective effect, we applied the metabolomics and transcriptomics profilings and focused on the expression patterns of genes that NA might alter, particularly those related to the accumulation of metabolites in the brain. According to the results, pathways related to neuroinflammation were significantly increased in LPS (lipopolysaccharide)-induced AD mice compared with the normal control, and pathways related to neuronal growth and synaptic plasticity were significantly downregulated. When NA was used for protection, these signaling pathways induced by LPS were partially reversed. At the same time, compared with the AD model group, upregulation of arachidonic acid metabolism, purine metabolism, and primary bile acid biosynthesis and downregulation of amino acid metabolic pathways were particularly pronounced in the NA treatment group. We also verified the enzymes of some metabolic pathways were consistent with transcriptome result. In summary, our results show that NA can significantly ameliorate LPS-induced neuroinflammation and deterioration of learning and memory, and exerts a neuroprotective function through regulation of multiple gene transcription and metabolism pathways. In particular, the arachidonic acid metabolism which related to inflammation and the amino acids metabolism which related to the synthesis of neurotransmitters were most significant response to NA treatment. Our results provided the first preliminary evidences for molecular mechanism investigation of NA from a combined transcriptome and metabolome perspective.