CCR5 as a key mediator: Insights into the molecular mechanisms by which air pollutants induce Alzheimer’s disease via network toxicology and molecular docking

BACKGROUND: Air pollution is a critical environmental risk factor for Alzheimer's disease (AD), yet the underlying molecular mechanisms remain unclear, hindering mechanistic insights and targeted prevention METHODS: This study combined network toxicology and molecular docking to explore how seven air pollutants (benzene, toluene, O₃, SO₂, NO, NO₂, CO) contribute to AD. Pollutant-related targets were retrieved from PubChem, SwissTargetPrediction, STITCH, and ChEMBL, while AD-related genes were sourced from GeneCards, OMIM, and TTD. Overlapping genes were identified, followed by GO and KEGG enrichment analyses. GEO dataset GSE122063 was used for differential expression and ROC curve-based diagnostic evaluation. Molecular docking assessed binding affinities between pollutants and core proteins. RESULTS: A total of 1349 pollutant-related targets and 495 AD-related targets were identified, with 88 overlapping genes. Enrichment analyses revealed significant involvement in neuronal apoptosis, inflammatory responses, and MAPK and PI3K-Akt signaling pathways. External validation identified CCR5, PLD3, CCL2, and RET as core targets, among which CCR5 demonstrated the highest diagnostic efficacy (AUC = 0.85). Docking simulations indicated that all seven pollutants could spontaneously bind to the core proteins (binding energy < 0 kcal/mol). Notably, benzene and toluene showed the strongest and most stable interactions with CCR5 (binding energy < -5 kcal/mol), suggesting that pollutant toxicity may be partly associated with direct binding to CCR5. CONCLUSIONS: This study supports CCR5 as a potential key molecular mediator associated with the link between air pollution and AD, providing a novel mechanistic perspective on how environmental pollutants may be involved in neurodegenerative disease. These findings offer theoretical support for further exploring CCR5-targeted preventive or therapeutic strategies.