Efficacy Evaluation And Potential Mechanism Study Of Aerobic Exercise Intervention In Alzheimer’s Disease Based On Evidence-Based Medicine And Bioinformatics

Objectives: To analyze the current status and hot areas of exercise intervention in Alzheimer’s disease(AD)through bibliometric and visualization methods;to systematically evaluate the effectiveness of aerobic exercise intervention in AD;to screen the core targets and signaling pathways of aerobic exercise intervention in AD based on text mining and bioinformatics;to construct and screen the "miRNA-mRNA" regulatory network;and to predict the potential mechanisms of action of aerobic exercise intervention in AD."To predict the potential mechanisms of aerobic exercise intervention in AD based on text mining and bioinformatics to screen the core targets and signaling pathways.Methods: 1.The literature related to exercise interventions in AD from China Knowledge Network,Wan Fang,Vipers,and Web of Science resource databases were searched by computer since their establishment to August 2022.Excel,knowledge graph analysis software VOSviewer and Cite Space were used to summarize and visualize the trends of publication volume,major journal sources,institutional distribution,national and author collaboration networks,keyword co-occurrence and timeline clustering.2.Randomized controlled trials(RCTs)with aerobic exercise interventions for patients with Alzheimer’s disease were obtained by searching CNKI,Wan Fang,VIP,China Biomedical Literature Service(CBM),Pubmed,Web of Science,Embase,Cochrane Library,and according to the The Physiotherapy Evidence Database(PEDro)scale was used to evaluate the quality of the literature of the included studies,and the software Revman 5.3 was used to perform meta-analysis of the included studies as well as subgroup analysis to find sources of heterogeneity;the software Stata 15.1 was used to test for publication bias.3.Database was searched by computer as above to collect basic research literature on AD intervention using aerobic exercise,to obtain differential target genes and differential miRNAs for aerobic exercise intervention in AD,and to predict potential target genes for differential miRNAs by two databases,miRWalk and Target Scan;in the disease databases Gene Cards,OMIM,TTD,the Drugbank,Pharm GKB and Dis Ge NET to obtain the causative target genes of human Alzheimer’s disease.The target genes obtained from text mining,the target genes obtained from miRNAs prediction and the AD target genes obtained from databases were intersected to obtain the potential target genes for aerobic exercise to intervene in human AD;the "protein-protein interaction" network was obtained from STRING website;the "protein-protein interaction" network was constructed using Metascape and bioinformatics online platform to construct "GO enrichment triple bar chart" and "KEGG enrichment bubble chart".Using KEGG color mapper tool to obtain KEGG pathways mapped by potential targets,import the correspondence files of miRNAs,target genes and KEGG pathways into Cytoscape 3.7.1software and construct "aerobic-miRNA-mRNA-pathway" network;using Cytohubba plug-in to screen core targets and find upstream miRNAs,construct "miRNA-mRNApathway" regulatory network of core targets.The Cytohubba plug-in was used to screen the core targets and search for upstream miRNAs to construct a core "miRNA-mRNA" regulatory network.Finally,the results of bioinformatics analysis were used to explore the potential mechanisms of aerobic exercise intervention in AD.Results: 1.In the bibliometric analysis,966 articles in Chinese and 934 articles in English were obtained.The results of keyword density map and time clustering map showed that aerobic exercise intervention for AD was an important research field at home and abroad.2.A total of 19 RCTs involving 979 patients were included.The results of Metaanalysis showed that compared with the control group,the aerobic exercise group had an increase in MMSE score(MD=2.11,95%CI[1.36,2.86])and a decrease in ADAS-Cog score(MD=-3.34,95%CI[-5.07,-1.60]).NPI score decreased(MD=-3.37,95%CI[-4.79,-1.95]),BI score increased(MD=4.97,95%CI[2.77,7.17]).3.The intersection of the target genes obtained by text mining,the target genes obtained by miRNAs prediction,and the AD pathogenic target genes obtained by database finally yielded 101 potential target genes for aerobic exercise intervention in human AD.The GO enrichment results showed that BPs were mainly enriched in regulation of protein hydrolysis,regulation of neuronal death,and positive regulation of catabolic processes.CCs were mainly enriched in early endosomes,neuronal cytosomes,and membrane microregions.MFs were mainly involved in ubiquitin protein ligase binding,amide binding,and protein structural domain specific binding.KEGG pathway analysis was mainly enriched in cancer pathway,lipid and atherosclerosis,and Alzheimer’s disease.Sclerosis,Alzheimer’s disease,Fox O signaling pathway,and autophagy pathway.The core targets obtained based on Cytohubba plug-in included APP,CASP3,BDNF,HIF1 A,VEGFA,STAT3,PPARG,IGF1,CREB1,SIRT1,and 9 upstream miRNAs associated with them to build a core "miRNA-mRNA regulatory relationship network".Conclusion: 1.In recent years,there has been some development in the field of exercise intervention in AD at home and abroad,especially in the field of aerobic exercise。2.The results of systematic evaluation showed that aerobic exercise can improve cognitive function,neuropsychiatric symptoms and activities of daily living in AD patients.3.Aerobic exercise intervention in AD may reduce Aβ deposition and Tau protein phosphorylation,decrease neuroinflammation and oxidative stress levels,improve autophagy,reduce apoptosis,and improve synaptic plasticity by regulating multiple core targets and pathways;the 11 pairs of "miRNA-mRNA" regulatory relationships successfully screened have,to some extent,elucidated the potential mechanism of action of aerobic exercise in the intervention of AD occurrence and development.