Silent information regulator 1: A potential target of semaglutide in the treatment of Alzheimer’s disease

doi:10.12307/2024.382

Abstract

Abstract: BACKGROUND: Studies have found that glucagon-like peptide-1 and its analogues have a significant neuroprotective effect, and some drugs have been applied to the clinical stage III study of Alzheimer’s disease. However, the mechanism of its neuroprotective effect is still unclear, which needs to be further explored and clarified.
OBJECTIVE: To screen out the genes related to the pathogenesis of Alzheimer’s disease and the related targets of semaglutide for the treatment of Alzheimer’s disease based on bioinformatics and network pharmacology analyses, to identify the potential target genes by comprehensive analysis of the two and to verify them at the cellular level.
METHODS: Using DisGeNET database, differentially expressed genes between Alzheimer’s disease patients and healthy population were screened out. The chemical structure formula and two-dimensional structure diagram of semaglutide were obtained using PubChem online database. GO/KEGG enrichment analysis was performed using DAVID online database. A protein-protein interaction network was constructed by using the STRING database. The HPA database was used to determine the distribution characteristics of the target proteins in various human tissues. Finally, western blot was used to detect relevant protein expression in HT22 cells after semaglutide intervention.
RESULTS AND CONCLUSION: With the dataset in DisGeNET database, 3 374 differentially expressed genes between Alzheimer’s disease patients and healthy people were obtained, and meanwhile, 101 target genes of semaglutide potential drugs were obtained. There were 23 intersection genes between them. Ten key genes were identified based on the protein-protein interaction network, which were silent information regulator 1 (SIRT1), CASP9, CCND1, CASP1, KEAP1, DLG4, CASP4, GRB2, GRIA1, and EDNRA. The results of GO gene functional annotation analysis of key genes showed that the positive regulatory activity of cysteine endopeptidase, the positive regulation of proteolysis, and the positive regulation of cysteine endopeptidase involved the cytoplasmic part of the apoptotic activity process; AMPA glutamate receptor complex, inflammatory complex, CARD domain binding, cysteine endopeptidase activity, and cysteine endopeptidase activity were involved in the apoptotic process. The results of KEGG signaling pathway analysis indicated that colorectal cancer, non-small cell carcinoma, and endometrial carcinoma were related to immune infiltration, inflammation and autophagic apoptosis. In addition, according to the association ranking of key genes and their distribution in different tissues of HPA online database, SIRT1 was identified as the most significant differential gene. The expression level of SIRT1 protein was significantly down-regulated in HT22 cells after β-amyloid protein 1-42 treatment, but it could be significantly increased after being treated with semaglutide. To conclude, SIRT1 may be a target gene for semaglutide in the treatment of Alzheimer’s disease.

Key words: DisGeNet database, Alzheimer’s disease, semaglutide, type 2 diabetes, bioinformatics, network pharmacology, silent information regulator 1

CLC Number:

Chai Shifan, Li Xinru, Ye Yucai, Sun Junli, Cai Hongyan, Wang Zhaojun. Silent information regulator 1: A potential target of semaglutide in the treatment of Alzheimer’s disease[J]. Chinese Journal of Tissue Engineering Research, 2024, 28(20): 3235-3239.

Figures/Tables 7

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