Integrating network pharmacology and multi-omics to explore the mechanism of Callicarpa kwangtungensis Chun in ameliorating Alzheimer's disease pathology in APP/PS1 mice.

Abstract

Callicarpa kwangtungensis Chun (CK) is a traditional herb for the treatment of blood stasis, hemostasis, anti-inflammation, and antidepressant. Previous studies showed that CK extract has significant anti-neuroinflammatory activity. However, the mechanism by which it treats AD is still unclear. This study aimed to investigate the effects and mechanisms of CK in ameliorating AD pathology using in vivo and in vitro models, supported by a multi-omics analysis approach. The chemical composition of CK was characterized using UPLC-QE Plus-MS/MS. The effects and mechanisms of CK on AD pathology were then investigated using APP/PS1 mice and BV2 and HT22 cell models, with comprehensive insights provided by network pharmacology, transcriptomics, and metabolomics analyses. This study is the first to report the identification of 146 compounds from CK. CK administration led to significant improvements in cognitive function, reduced amyloid-beta and neurofibrillary tangle formation, and inhibited the activation of microglia and astrocytes in APP/PS1 mice. Comprehensive analyses suggest that CK may modulate the TCA cycle through the PI3K-AKT signaling pathways and inflammation-related MAPK and NF-κB signaling pathways. In vitro studies revealed that CK significantly inhibited LPS-induced inflammation and oxidative stress in BV2 cells, as well as reduced oxidative stress and neuronal apoptosis in HT22 cells. These findings underscore the potential of CK as a therapeutic agent in alleviating AD pathology. This study offers new insights into CK's mechanisms, suggesting that its therapeutic effects may be achieved through the coordinated reduction of neuroinflammation, oxidative stress, and neuronal apoptosis across multiple pathways, collectively working to counteract AD pathology.