Study on the Mechanism of Ginkgetin's Anti-alzheimer's Disease Effects Based on Network Pharmacology and Experimental Validation
Xin-Juan Liu, Ting Yu, Mei-Fang Jiang, Dan-Dan Wang, Yan-Jia Liu, Guo-Qin Zhu, Yan Zhao, Xing-Yu Wang, Ying XuIntroduction:
Ginkgetin (GIN) has been reported to exhibit antioxidant and antiinflammatory activities, but its role in Alzheimer's Disease (AD) remains underexplored. This study aimed to systematically investigate the mechanisms of GIN in AD by integrating network pharmacology for target prediction with molecular docking, behavioral assays, and molecular experiments.
Methods:
Network pharmacology techniques were employed to predict the potential targets of GIN, and pathways were identified through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Molecular docking was used to assess the binding capacity between GIN and predicted targets. Furthermore, Zebrafish behavioral experiments and PC12 cell-based molecular assays were conducted to evaluate GIN’s pharmacological effects.
Results:
43 common targets for GIN were identified across four databases, with GSK3β being a key hub target. Pathway analysis showed GIN’s involvement in glutamatergic synapse and AD-related neurological signaling. Molecular docking revealed strong binding of GIN to AD-associated targets (bace1, ps1/2, gsk3β, cdk5) with binding energies < -5.0 kcal/mol. In zebrafish, GIN significantly ameliorated AlCl3-induced behavioral deficits by inhibiting Acetylcholinesterase (AChE) activity and downregulating bace1, ps1/2, gsk3β, and cdk5. In PC12 cells, GIN reversed Aβ1-42-induced upregulation of BACE1, PS1/2, GSK3β, and CDK5 at both mRNA and protein levels, while suppressing p-tau hyperphosphorylation.
Discussion:
GIN's anti-AD effects may stem from its multi-target regulation: it targets key AD-related molecules and modulates critical pathways, supported by both in silico and experimental evidence. The consistency between molecular and behavioral results confirms its potential as an AD intervention.
Conclusion:
This study confirmed the anti-AD effects of GIN in zebrafish and PC12 cells, revealing its multi-mechanism protective effects and providing theoretical and experimental support for further research on GIN.