SMND-309 Attenuated The Cognitive Deficits Caused By Lipid Droplets Accumulation In Neurocytes Of Mice With OSAS

Study objectives:Chronic intermittent hypoxia is one of the important characteristics of obstructive sleep apnea.It can cause cognitive deficits,however,the mechanism remains unclear.As the product of oxidative stress,ROS participate in a variety of neurodegenerative diseases,especially obstructive sleep apnea.Studies showed that ROS-induced neuron damage through promoting the accumulation of lipid droplets in neurocytes.To expose the role of lipid droplet accumulation in chronic intermittent hypoxia-induced cognitive deficits,the level of ROS and the lipid droplet accumulation in hippocampus were detected after chronic intermittent hypoxia treatment.Methods:Thirty-two male C57BL/6 mice,6 weeks of age,were randomly divided into 4 groups.The two groups of WT CIH mice and SMND-309 CIH mice were treated with chronic intermittent hypoxia for 12 weeks,while the other two groups of WT mice and SMND-309 mice were kept in normal oxygen chamber.During the last week of the treatment,SMND-309 mice and SMND-309 CIH mice were intraperitoneal injected with SMND-309 on a daily basis.Three-chamber social test,morris water maze and fear conditioning test were conducted in succession after treatment.H&E staining and electron microscopy experiment were preformed to investigate the pathological changes of hippocampus.To prove the existence of lipid droplets in neurocytes,the fluorescent dyes Nile red and BODIPY(493/503)were used.The possible molecular mechanism of lipid droplets accumulation was uncovered by ROS kit and western blot.The lipid peroxidation on neuron degeneration was then explored by C11-BODIPY(581/591).Results:After 12 weeks CIH treatment,the social novelty discrimination,fear memory,spatial learning and memory were significantly injured.H&E staining and electron microscopy experiment showed that seldom neural progenitor cells existed in SGZ of the DG area,along with disarranged and hydropic neurons in the CA1 region.Glia was also edema with lipid droplet accumulation.Consisted with these pathological changes,elevated ROS facilitated LDs accumulation by activating JNK/SREBP.Lipids were also peroxided by the high level of ROS,which aggravated neurodamage and cognitive deficits.Conclusion:SMND-309 treatment reducing ROS induced-LDs accumulation in neurocytes and ameliorated the pathologic injuries caused by CIH treatment,which improved the cognitive deficits of CIH mice.