The efficacy and pharmacological mechanism of Guilingji to prevent Alzheimer's disease.

BACKGROUND: Effective treatments for Alzheimer's disease (AD) are limited, so preventing or delaying its onset is crucial. Previous clinical trials have shown the safety and potential efficacy of the Chinese herbal formula Guilingji (GLJ), but its preventive effect on AD and mechanism are still unclear. METHODS: In this study, a network pharmacology approach was employed to elucidate the mechanism of GLJ in AD. Behavioral assessments and biochemical experiments were conducted on APPswe/PS1ΔE9 transgenic (APP/PS1) mice. The pivotal pathways and biological processes were validated in vitro AD model using HT22 and BV-2 cells stimulated by Aβ1-42. Additionally, molecular docking was utilized to illustrate the binding affinity of GLJ's active components to key genes implicated in AD prevention. RESULTS: Network pharmacology analysis identified 482 common targets associated with the active components of GLJ. KEGG enrichment analysis highlighted the PI3K-AKT and retrograde endocannabinoid signaling pathways as the key mechanisms. GLJ significantly postponed cognitive decline, suppressed Aβ plaque accumulation, mitigated neuronal damage, and reduced inflammatory responses in glial cells in AD mice. GLJ and its compounds quercetin and carvone assist in neuron survival by regulating the PI3K/AKT pathway and the apoptotic proteins Bcl-2 and Bax. Additionally, GLJ, kaempferol and stigmasterol enhance microglial clearance of Aβ through the CB2 receptor. Moreover, molecular docking suggested that quercetin and carvone interacted effectively with PI3K, while kaempferol and stigmasterol combined well with CB2. CONCLUSIONS: GLJ effectively delays AD progression by modulating critical pathological pathways such as neuronal survival, neuroinflammation, and Aβ clearance through a synergistic multi-target approach, offering a promising avenue for AD prevention.