Multi-Omics Study Of Sleep Deprivation In Relation To Alzheimer’s Disease And Its Molecular Mechanisms

Background: Chronic sleep disorders and sleep cycle disorders can cause a variety of diseases,and studying the effects of transient sleep cycle disorders on multi-omics molecules in human peripheral blood will help to provide important molecular targets for the discovery and treatment of these diseases.In addition,sleep disorders have been found to be one of the early manifestation symptoms of neurodegenerative diseases,and therefore therapeutic measures targeting sleep disorders are important for the prevention and amelioration of neurodegenerative diseases.Melatonin,an amine hormone that regulates the circadian clock and sleep cycle,has been studied for the treatment of Alzheimer’s disease(AD).However,there is a lack of research on the effects of melatonin on mitophagy in AD so far.Objective: Multi-omics were used to reveal the blood molecular profiles of people suffered short-term sleep deprivation,and explored the changes of melatonin level and corresponding correlated molecular network during this period.Finally,the effect of melatonin on mitophagy and its possible mechanisms were investigated in AD model mice.Methods: Healthy male and female volunteers between the ages of 20-30 years were recruited to simulate transient sleep disorders with sleep deprivation for 24 hours.The experiment started with fasting venous blood collection at 8:30 am on the first day,followed by sleep deprivation for 24 hours.A second fasting venous blood collection at 8:30 am on the second day,followed by rest and recovery.Finally,a third fasting venous blood collection at 8:30 am on the third day.The obtained blood samples were subjected to mononuclear cell transcriptomics,plasma proteomics,and plasma metabolomics,respectively.For studying the effects of melatonin on AD mitophagy,4-month-old 5×FAD transgenic mice were treated with melatonin by gavage for one month,and then the behavior,pathology and hippocampal proteomic were analysed.The effect of melatonin on mitophagy in 5×FAD transgenic mice was reversely verified with the autophagy inhibitor chloroquine(CQ).Results: Transient sleep deprivation led to an increase in the number of most immune cells in the blood and an increase in plasma levels of inflammatory factors.Bioinformatics analysis showed that a large number of differential multi-omics molecules were associated with immune processes,among which neutrophil-mediated immune processes were the most prominent.Multi-omics association analysis also demonstrated the predominance of immune processes after sleep deprivation.In addition,the level of melatonin was significantly reduced after sleep deprivation,and the differential multi-omics molecules correlated to melatonin were also enriched in AD signaling pathway.Therapeutic experiments with melatonin showed that melatonin improved learning and memory ability of 5×FAD transgenic mice,and attenuated the deposition of Aβ plaques.Proteomics,immunoblot analysis and chloroquine treatment demonstrated that melatonin may promote the fusion of autophagosomes with lysosomes by upregulating the expression of Mucolipin-1(Mcoln1),which in turn reverses the mitophagy impairment in the brain of 5×FAD transgenic mice.Conclusion: The main changes caused by short sleep stripping were the disturbance of immune function,followed by the potential occurrence of neurodegenerative diseases,and these harmful effects were difficult to recover for at least one day.In addition,the reduction of melatonin levels caused by transient sleep deprivation,and the positive effect of melatonin in the treatment of AD model mice,suggested that melatonin may be a drug candidate for the prevention or treatment of AD.