Neuronal and Astrocytic Lipid Metabolic Coupling Mediates Ozone-Induced Learning and Memory Impairment

Abstract

Surface ozone (O₃) induces chronic oxidative stress and lipid peroxidation in the brain, increasing the risk of neurodegenerative disease. Lipid metabolic coupling between neurons and astrocytes is vital for brain health. However, its response to O₃-induced oxidative stress remains largely unexplored. In this study, subacute O₃ exposure (0.5 or 1.5 ppm, 4 h/day, for 28 days) resulted in learning and memory impairments, accompanied by neuronal loss, glial cell activation, neuroinflammation, and lipid peroxidation in mice. An important outcome of exposure to reactive oxygen species (ROS) generated by O₃ is the buildup of lipid droplets in the astrocytes. Interestingly, in neurons, O₃ exposure activates c-Jun N-terminal kinase and sterol regulatory element-binding protein, promoting lipogenesis. As cells attempt to cope with this stress, O₃ interferes with the liver X receptor/apolipoprotein E/ATP-binding cassette transporter A1 pathway in astrocytes, reducing the efficiency of lipid transport from neurons to astrocytes. This imbalance─where the astrocytic transport machinery fails to compensate for accelerated neuronal lipid synthesis─leads to a breakdown of lipid detoxification processes. Meanwhile, impaired expression of genes related to lipid degradation exacerbates O₃-induced lipotoxicity and neuronal damage. Supplementation with N-acetylcysteine or citicoline sodium mitigated the O₃-induced disordered lipid metabolism and learning and memory impairments. This study highlights the role of neuron-astrocyte lipid metabolic coupling in mediating O₃-induced neurotoxicity and offers a potential approach for addressing O₃ pollution-induced neurodegenerative diseases.