Isobavachalcone ameliorates Alzheimer disease pathology by autophagy-mediated clearance of amyloid beta and inhibition of NLRP3 inflammasome in 5XFAD mice

Abstract

Abstract The complex pathology of Alzheimer disease (AD) has led to failure of multiple drugs in clinical trials. We hypothesized that targeting multiple aspects AD pathology may yield better results. Therefore, we identified isobavachalcone (IBC) as a natural compound with dual activity against AD pathology. IBC caused AMPK phosphorylation through CAMKK2 to induce autophagy and inhibit NLRP3 inflammasome in primary astrocytes. The inhibition of NLRP3 inflammasome by IBC was completely reversed when autophagy was inhibited by siAMPK or bafilomycin A1. Further, the primary astrocytes treated with IBC showed a significant intracellular clearance of amyloid beta, which was added externally to the culture. However, when autophagy was inhibited by siRNA-mediated downregulation of AMPK, the clearance of amyloid beta was significantly reduced. Moreover, the inflammatory phenotype of astrocytes also displayed a sharp decline, as indicated by the reduced levels of GFAP and IL-1β. We validated the anti-Alzheimer effect of IBC by treating transgenic 5XFAD mice for two months with IBC. The 5XFAD mice showed a significant improvement in brain health as indicated by improved memory behavior in the radial arm maze test, along with better performance in the open field and rotarod tests. The data revealed that IBC upregulated the autophagic proteins, which led to decreased levels of amyloid beta in the brain and plasma, which further led to reduced levels of neuroinflammation and improved brain health. This study highlights the importance of autophagy in the simultaneous clearance of amyloid beta and inhibition of NLRP3 inflammasome to ameliorate AD pathology.