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.

• Authors: Dongze Li, Na Xu, Yanyan Hou, Wenjing Ren, Na Zhang, Xi Wang, Yeying Sun, Wenxue Lu, Guiwu Qu, Yan Yu, Changjun Lv, Fang Han
• Journal: Molecular medicine (Cambridge, Mass.) (Mol Med) Vol. 28 Issue 1 Pg. 3 (01 14 2022) ISSN: 1528-3658 [Electronic] England
• PMID: 35030992 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• 2-(6-(2-carboxyvinyl)-2,3-dihydroxyphenyl)-3-(3,4-dihydroxyphenyl)acrylic acid
• Caffeic Acids
• Eye Proteins
• GTP-Binding Protein Regulators
• Phosphoproteins
• Reactive Oxygen Species
• Sterol Regulatory Element Binding Proteins
• phosducin
• Pdp1 protein, mouse
• Protein Phosphatase 2C
• Acetyl-CoA Carboxylase

Topics

• Acetyl-CoA Carboxylase (metabolism)
• Animals
• Caffeic Acids (pharmacology)
• Cognition
• Cognitive Dysfunction
• Disease Models, Animal
• Eye Proteins (metabolism)
• GTP-Binding Protein Regulators (metabolism)
• Hippocampus (metabolism)
• Hypoxia (metabolism)
• Learning
• Lipid Droplets (metabolism)
• Lipid Peroxidation
• MAP Kinase Signaling System
• Memory
• Mice
• Neurons
• Phosphoproteins (metabolism)
• Protein Phosphatase 2C (metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• Sleep Apnea, Obstructive (diagnosis, drug therapy, etiology, metabolism)
• Sterol Regulatory Element Binding Proteins (metabolism)