Potential small-molecule compounds and targets for Alzheimer's disease: Integrating bioinformatics analysis and in vitro verification

Abstract

Objective

Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by progressive memory decline and cognitive dysfunction. The specific pathogenesis of AD remains unclear. This study aimed to explore the crucial genes and therapeutic small-molecule compounds in AD via integrated bioinformatics analysis, molecular docking, and in vitro verification.

Methods

The gene dataset GSE122063, including 12 samples from patients with AD and 11 non-demented control samples, was downloaded from the Gene Expression Omnibus (GEO) database. The online tool GEO2R was used to analyze differentially expressed genes (DEGs). Functional enrichment analysis of the DEGs was performed using DAVID and ClueGo databases. A protein-protein interaction network was constructed using the STRING database and visualized in Cytoscape. Potential small-molecule compounds for AD therapy were screened using the Connectivity map database. The crucial genes in a rat model of AD were confirmed by RT-PCR. Molecular docking of the screened crucial genes and small-molecule compounds was further performed to identify potential therapeutic drugs for AD.

Results

A total of 1145 DEGs were identified, which were enriched in intracellular protein transport, cell cycle, establishment of protein localization to membrane, and so on. Eight hub genes, including RPS29, CREBBP, ANAPC10, ANAPC4, MAGOHB, TCEB2, RPL10A, and SEC61A1, were identified in the protein-protein interaction network. The MAPK signaling pathway was closely related to AD. Furthermore, increased expression of CREBBP was confirmed in the rat model of AD, and molecular docking revealed that CREBBP exhibited the strongest binding affinity with prochlorperazine.

Conclusion

CREBBP was identified as a crucial hub gene and might serve as a potential target for AD. Prochlorperazine, which exhibited strong binding to CREBBP, showed potential as a therapeutic drug in AD.