Pathway-based network medicine identifies novel natural products for Alzheimer's disease

Natural products exhibit potential as candidates for developing multi-target agents for Alzheimer's disease treatment. The aim of this study is to utilize network-based medicine to identify novel natural products for Alzheimer's disease, and investigate their efficacy and mechanisms of action. In this study, we identified (-)-Vestitol and Salviolone as new potential natural products for treating Alzheimer's disease via an Alzheimer's disease-related pathway-gene network. Both natural products improved the cognition of APP/PS1 transgenic mice, reduced Aß deposition, and lowered soluble toxic Aß levels in the brain. Notably, a synergistic effect was observed when the two natural products were combined. Transcriptomic analysis and qRT-PCR experiments revealed that the synergistic mechanism of (-)-Vestitol and Salviolone combination is associated with the regulation of a broader range of AD-related pathways and genes, particularly the neuroactive ligand-receptor interaction pathway and calcium signaling pathway. Overall design: To investigate the mechanism of the synergistic effect of the combination of (-)-Vestitol and Salviolone, APP/PS1 transgenic mice were randomly assigned to each of five groups (n = 8 per group), and eight C57BL/6J mice were assigned as wild type group. These groups were intraperitoneally administered with vehicle, (-)-Vestitol, Salviolone, (-)-Vestitol and Salviolone, and Donepezil. The brain cortex of wild type group, control group, (-)-Vestitol group, Salviolone group, and combination group (n = 5 per group, randomly selected) were used to perform RNA-seq for analyzing gene expression differences of control group compared to wild type group, and treatment groups compared to control group.