Integrating machine learning and experiments to elucidate the potential molecular mechanisms of methylparaben-induced Alzheimer's disease: evidence from a Tau hyperphosphorylation cell model.

BACKGROUND: Alzheimer's disease (AD) was a progressive neurodegenerative disorder characterised by an insidious onset and gradual cognitive decline. It remained a significant global health challenge. Methylparaben (MEP), a preservative commonly used in cosmetics and food processing, had been associated with the development and progression of AD. METHODS: First, we acquired the initial three-dimensional (3D) structure of MEP from PubChem (CID: 7456), followed by structural optimization via energy minimization using Chem3D software to complete its 3D structural characterisation. This was followed by systematic target prediction across the SwissTargetPrediction, SEA, GeneCards and OMIM databases. We then constructed protein-protein interaction (PPI) networks using STRING and visualised them in Cytoscape to identify core targets. Molecular docking simulations using CB-Dock2 elucidated the binding affinities between MEP and the key proteins. Experimental validation combined Gene Expression Omnibus (GEO) database analysis with quantitative reverse transcription polymerase chain reaction (qRT-PCR) to quantify transcriptional changes in SK-N-SH neural cells. RESULTS: A total of 153 potential targets associated with MEP and AD were identified. Ten core targets were determined through screening using the STRING platform and Cytoscape software, including HIF1A, IGF1R, PDGFRB, PTK2, VCAM1, CXCL12, ERBB2, ESR1, JAK2 and BCL2L1. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that the core MEP targets in AD primarily concentrate on the following key signalling pathways: Neuroactive ligand-receptor interactions, EGFR tyrosine kinase inhibitor resistance, HIF-1 signalling pathway and gamma-aminobutyric acid (GABA) synapse. Molecular docking simulations using CB-Dock2 confirmed a high binding affinity between MEP and these core targets. To investigate the mechanism of action of MEP, we validated the findings using clinical datasets and the human neuroblastoma cell line SK-N-SH. Upregulation of ten transcriptional expressions was observed, suggesting that MEP might influence cognitive function in patients with AD. CONCLUSION: This study elucidated the potential molecular mechanisms of MEP in the progression of Alzheimer's disease-related tau pathology, offering new insights for the prevention and intervention of degenerative diseases that might be triggered by excessive exposure to MEP environments.