Exploring The Mechanism Of Action Of Quercetin From Roxburghii In The Intervention Of Alzheimer's Disease Mice Based On Multi-omic

Rosa roxburghii Tratt(RRT),as a special advantageous fruit in Guizhou province,is rich in many functional ingredients.The group has found that RRT quercetin has antioxidant and anti-inflammatory activities and has alleviating effects on symptoms associated with aging mice,but little is known about the alleviating effects of oxidative stress,inflammation and cholinergic neurotransmitters caused by AD during progressive development,and its metabolic pathways and mechanisms of action are not yet clear.Based on this,the present study focused on the effects of RRT quercetin on AD mice,and further combind with the histological approach to explore the interconnection between genes and metabolites of RRT quercetin intervention in AD brain tissue,and to investigate the potential metabolic changes and possible molecular mechanisms.At the same time,the regulatory effects of RRT quercetin on the intestinal flora and intestinal metabolism of AD were examined.The main findings are as follows :(1)Study on the intervention effect of RRT quercetin in AD mice.The mice were induced by D-galactose combined with aluminum for 12 weeks to establish AD model mice.The cognitive function of AD mice was detected by water maze test,and the physiological and biochemical indexes of serum and brain tissue samples were measured in each group of mice,and the pathological changes of brain tissue were observed by HE staining.The results showed that the brain function indexes,antioxidant enzyme levels,inflammatory factors,ACh content and Ch AT activity were significantly decreased,while MDA content and ACh E activity were significantly increased in AD mice.These indicators were improved after the RRT quercetin intervention.The results of HE staining showed that the cerebral cortex and hippocampus of AD mice had lighter staining,tissue softening,a large number of neurons shrinkage and edema.After the intervention of RRT quercetin,the pathological degree of brain tissue in AD mice was alleviated.In summary,RRT quercetin has an improvement effect on AD mice.(2)Transcriptomic study of RRT quercetin on brain tissue of AD mice.Through the study of brain tissue transcriptomics,it was found that RRT quercetin changed the expression levels of 23 key genes related to AD mice.Among them,PI3 K,PKB/Akt,GSK-3β,β-catenin,GPX1,AMPK,α-7n ACh R,Bcl-2,CAT,Ch AT,NOS,FOXO1,p38 MAPK and other genes were significantly up-regulated,NF-k B,Wnt,IL-6,IL-1β,TNF-α,JAK2,MEK,ERK,ACh E and other genes were significantly down-regulated.It is suggested that RRT quercetin mainly interferes with the development of AD disease by regulating biological processes such as neurotransmitter binding,lipid metabolism and arachidonic acid binding.(3)Metabolomics study of RRT quercetin on brain tissue of AD mice.Through the study of brain tissue metabolomics,it was found that RRT quercetin could change the expression level of endogenous metabolites in AD mice.Nine differential metabolites of arachidonic acid,cholesterol,choline,25-hydroxycholesterol,β-alanine,5-hydroxyindoleacetic acid,N-hydroxyacetic acid neuraminic acid,riboflavin and thiamine were screened in the brain tissue,suggesting that RRT quercetin may play an intervention role mainly by regulating disordered amino acid metabolism,lipid metabolism,glucose metabolism and nucleic acid metabolism.In addition,through the joint analysis of differential metabolites and differential genes,it was found that the key metabolites riboflavin,thiamine,choline,25-hydroxycholesterol,and key genes Akt,Nrf2,MAPK,and NF-k B had strong correlation.The key genes were verified by RT-PCR and Western Blot.It was found that RRT quercetin may interfere with oxidative stress injury and inflammation caused by AD mice during progressive development by mediating Nrf2 pathway and PI3K-Akt/NFk B/p38 MAPK pathway.(4)Effects of RRT quercetin on intestinal flora and intestinal metabolomics in AD mice.Through the study of 16 S r RNA high-throughput sequencing technology and metabolomics technology of cecal contents,it was found that RRT quercetin could significantly improve the α diversity of intestinal flora in AD mice.At the phylum level,it was found that the dominant bacteria Bacteroidetes and Firmicutes accounted for more than70% of the total bacteria in each group.At the genus level,after the intervention of RRT quercetin,the dominant genera such as Bacteroides,Blautia,Corynebacterium,Staphylococcus and Lactobacillus were all reversed,indicating that RRT quercetin can regulate the intestinal flora of AD mice,increase the richness of beneficial bacteria and reduce the richness of pathogenic bacteria.A total of 23 differential metabolites such as L-aspartic acid,2-deoxypantothenic acid,thiamine,L-glutamic acid,guanine,1,5-naphthalenediamine,and nonanoic acid were screened by intestinal metabolomics.Combined with the analysis of intestinal flora and differential metabolites,it was found that the metabolites cytidine,phenylacetic acid,quinolinic acid,nonanoic acid and xanthate were closely related to the intestinal flora,suggesting that RRT quercetin mainly improved the intestinal metabolic disorder of AD mice by regulating its metabolites-related nucleotide metabolic pathway and amino acid metabolic pathway.