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

The mechanisms of chronic intermittent hypoxia (CIH)-induced cognitive deficits remain unclear. Here, our study found that about 3 months CIH treatment induced lipid droplets (LDs) accumulation in hippocampal nerve and glia cells of C57BL/6 mice, and caused severe neuro damage including neuron lesions, neuroblast (NB) apoptosis and abnormal glial activation. Studies have shown that the neuronal metabolism disorders might contribute to the CIH induced-hippocampal impairment. 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 nerve and glia cells. ACC catalyzed the carboxylation of Acetyl-CoA to malonyl-CoA and then more lipid acids were synthesized, which finally caused aberrant LDs accumulation. Therefore, the JNK/SREBP/ACC pathway played a crucial role in the cognitive deficits caused by LDs accumulation after CIH exposure. Additionally, LDs were peroxidized by the high level of ROS under CIH conditions. Together, lipid metabolic disorders contributed to nerve and glia cells 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.

LDL exposure disrupts mitochondrial function and dynamics in a hippocampal neuronal cell line

“…In health conditions, neurons do not present high lipid droplet contents since they have a lower capacity to use lipids for energy production [52]. However, lipid droplets are increased in neurons in several neurodegenerative diseases [53][54][55][56], and it is associated with cognitive impairment [57].…”

Association Between Sleep Apnea Syndrome and Osteoarthritis: Insights from Bidirectional Mendelian Randomization and Bioinformatics Analysis

“…38 Chronic hypoxia in SAS leads to the production of a large amount of reactive oxygen species (ROS), activating the JNK/SREBP/ACC pathway in neurons and glial cells, ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, thereby leading to an increase in fatty acid synthesis and abnormal accumulation. 39 In OA, changes in lipid metabolism may be a cause of the disease, studies have observed lipid deposition in joints before histological changes occur, proteomic analysis has revealed significant connections between OA and lipid metabolism, with adipokines identified as key regulatory factors in the pathogenesis of OA. 40 In-depth future research into TNF, IL-17, and lipid metabolism pathways could offer a valuable theoretical foundation for treating the comorbidity of OA and SAS.…”