Integrating network pharmacology and experimental validation to uncover the mechanisms of Ganoderma lucidum in ameliorating neuroinflammation in Alzheimer's disease.

OBJECTIVES: This study aimed to explore the anti-neuroinflammatory mechanism of Ganoderma lucidum against Alzheimer's disease (AD) using network pharmacology and molecular docking, and verify its neuroprotective and anti-neuroinflammatory effects in Aβ1-42-induced AD mice. METHODS: Common targets were screened and analyzed by KEGG/GO enrichment. Core targets were evaluated by molecular docking and dynamics simulation. Aβ1-42-induced AD mice and LPS-stimulated macrophages were used. Cognitive function, Aβ deposition, tau phosphorylation, and inflammatory gene expression were measured. KEY FINDINGS: Network analysis highlighted inflammation-related pathways. Molecular dynamics simulations confirmed stable binding between active components and targets like STAT1, STAT3, JAK2, and TNF. In vivo, G. lucidum extract suppressed abnormal activation of microglia and astrocytes, and reduced pro-inflammatory factors. Following G. lucidum administration, mRNA levels of Jak2 and Stat1 in hippocampal tissue were significantly reduced, suggesting potential regulation of neuroinflammation via the JAK2/STAT1 pathway. Concurrently, G. lucidum down-regulated transcription of key subunits (Ncstn, Aph-1, Pen-2) in the γ-secretase complex, thereby reducing Aβ1-42 production. In vitro experiments similarly confirmed G. lucidum's ability to inhibit LPS-induced IL-6 and TNF-α release from macrophages. CONCLUSIONS: Ganoderma lucidum extract alleviates neuroinflammation in AD models, providing experimental evidence for its potential application in AD prevention or therapy.