Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder that occurs with aging. Ganoderma lucidum (Curtis.) P. Karst. (G. lucidum) is a traditional medicinal fungus believed to nourish the brain and anti-aging. Ganoderic acid A (GAA), a triterpenoid from G. lucidum, has demonstrated natural neuroprotective effects. This study aims to explore the therapeutic effect and molecular mechanism of GAA on AD. Systematic network pharmacology identified 95 targets, 8 biological functions, and multiple pathways. The results highlighted MAPK family members as core genes, with MAPK1 (ERK2) showing the highest binding affinity to GAA in molecular docking. In vitro experiments revealed that GAA dose-dependently increased the viability of Aβ_25-35-injured HT22 cells and inhibited MAPK pathway-related protein expression. Similar to FR180204, 100 μM GAA significantly reversed ERK protein expression, oxidative stress markers, and mitochondrial damage in AD cell model. GAA also downregulated cleaved caspase-3 protein levels, apoptosis rates, Aβ and p-Tau expression by inhibiting the ERK signaling pathway. The therapeutic effect of GAA on AD was predicted and validated through network pharmacology and in vitro experiments. The ability of GAA to inhibit apoptosis via the ERK/MAPK signaling pathway positions it as a promising candidate for AD treatment.