ABSTRACT Studies have demonstrated that accumulation of formaldehyde (FA) in the body can result in Alzheimer's disease (AD) like changes including cognitive impairment, Aβ deposition, and Tau hyperphosphorylation. Mangiferin (MGF), a natural flavonoid compound, has been suggested in previous reports to have potential in the treatment of AD. This study integrated network pharmacology and in vivo experiments to elucidate the therapeutic potential and mechanisms of MGF in mitigating FA‐induced neurotoxicity. Potential overlapping targets between MGF and AD were identified using jvenn. Functional enrichment analysis of these targets was performed with DAVID. A protein–protein interaction (PPI) network was constructed using STRING and visualized in Cytoscape to identify hub genes. Molecular docking simulations with AutoDock were then employed to assess binding affinity. Subsequently, for experimental validation, a mouse model of FA‐induced neurotoxicity was established. Spatial memory and cognitive function in mice were evaluated using the Y‐maze and novel object recognition tests. The expression levels of key pathway‐related proteins in the cortex and hippocampus were analyzed via immunohistochemistry (IHC) and Western blotting (WB). Network analysis identified AKT1 and GSK3β as key targets, and molecular docking confirmed strong binding affinity between MGF and these proteins. Experimental validation demonstrated that MGF dose‐dependently improved spatial memory and cognitive performance in FA‐exposed mice, reduced neuronal apoptosis, and suppressed Tau hyperphosphorylation at Thr181, Ser396, and Ser404. Mechanistically, MGF activated the PI3K/AKT pathway, leading to GSK3β inactivation through Ser9 phosphorylation. These findings highlight MGF as a promising therapeutic candidate for AD by targeting the PI3K/AKT/GSK3β axis.
Wang et al. (Thu,) studied this question.