Alzheimer's disease (AD) is a severe neurodegenerative disorder, with persistent neuroinflammation and impaired autophagy recognized as key contributing factors. CCA is a naturally occurring cassane diterpene compound derived from the seed of Caesalpinia bonduc. Our research is the first to explore the role and mechanism of CCA in treating Alzheimer's disease. We assessed the levels of pro-inflammatory cytokines and autophagy in BV2 cells following lipopolysaccharide (LPS) treatment and anti-neuroinflammatory effects of CCA were evaluated in LPS-induced mice, with the underlying mechanisms explored using transcriptomic. Additionally, we examined the cognitive-enhancing effects of CCA in APP/PS1 mice and investigated Caesalpinia bonduc associated molecular mechanisms through proteomic analysis, immunohistochemistry (IHC) and immunofluorescence (IF) assays. Finally, the molecular target of CCA was validated using molecular dynamics simulations and cellular thermal shift assay (CETSA). CCA can down-regulate the mRNA levels of inflammatory factors in BV2 cells stimulated by LPS, and has good permeability of blood-brain barrier. Furthermore, CCA ameliorated cognitive impairment and neuronal damage in both LPS-induced and APP/PS1 mice. And demonstrated that CCA mitigates neuroinflammation by driving microglial polarization from M1 to M2, a process potentially mediated by the AMPK/NF-κB pathway, thereby reducing tau pathology. Proteomic profiling and IHC revealed that CCA upregulates FOXG1 expression in APP/PS1 mice. Furthermore, the scTenifoldKnk confirmed that AMPK has a significant impact on the regulation of autophagy and inflammation response. Our findings verified that CCA exhibits anti-neuroinflammatory activity by AMPK/NF-κB pathway and activates autophagy via the AMPK-mTOR-FOXG1 signaling axis, which underscores its potential as a novel therapeutic option for the treatment of AD.
