Abnormal Lipid Droplets Accumulation Induced Cognitive Deficits in Obstructive Sleep Apnea Syndrome Mice via JNK/SREBP/ACC Pathway but Not Through PDP1/PDC Pathway
Abstract IntroductionThe mechanisms of chronic intermittent hypoxia (CIH)-induced cognitive deficits remain unclear. Studies have shown that the neuronal metabolism disorders might contribute to the CIH induced-hippocampal impairment. MethodsWe assessed the CIH exposure influences of C57BL/6 mice on the activity of nerve, measured projects related to lipid metabolism, and treated with drugs SMND-309. ResultsOur study found that 12 weeks CIH treatment induced lipid droplets (LDs) accumulation in hippocampal neurocytes of mice, and caused severe neuro damage including neuron lesions, neuroblast (NB) apoptosis and abnormal glial activation. Mechanistically, the results showed that pyruvate dehydrogenase complex E1ɑ subunit (PDHA1) and the pyruvate dehydrogenase complex (PDC) activator pyruvate dehydrogenase phosphatase 1 (PDP1) did not noticeable change after intermittent hypoxia. Consistent with those results, the level of Acetyl-CoA in hippocampus did not significantly change after CIH exposure. Interestingly, we found that CIH produced large quantities of ROS, which activated the JNK/SREBP/ACC pathway in neurocytes. ACC catalyzed the carboxylation of Acetyl-CoA to malonyl-CoA and then more lipid acids were synthesized, which finally caused aberrant LDs accumulation. Additionally, LDs were peroxidized by the high level of ROS under CIH conditions. An active component of Salvia miltiorrhiza, SMND-309, dramatically alleviated these injuries and improved cognitive deficits of CIH mice. ConclusionTherefore, the JNK/SREBP/ACC pathway played a crucial role in the cognitive deficits caused by LDs accumulation after CIH exposure. Together, lipid metabolic disorders contributed to neurocytes damage, which ultimately caused behavioral dysfunction. An active component of Salvia miltiorrhiza, SMND-309, dramatically alleviated these injuries and improved cognitive deficits of CIH mice.