Acteoside Repressed Microglia M1 Polarization Through Inhibited NF-κB Signalling Pathway and AMPK-Mediated Mitochondria Function Recovery

Abstract

Background: Alzheimer's disease (AD) is the most frequent type of dementia. While acteoside (ACT), a compound isolated from Cistanche tubulosa, possesses neuroprotective properties. However, the underlying mechanism in regulating microglia polarization remains ill-defined. Methods: Herein, AlCl3-induced AD model in zebrafish larvae was applied to uncover the therapeutic efficacy of ACT. BV-2 cells were used to demonstrate the role of ACT on microglia polarization. RNA-Sequence, HPLC-Q-TOF-MS, western blot and molecular docking were combined to confirm its mechanism. Results: ACT significantly ameliorated the experimental dyskinesia and nervous system disorders in zebrafish. Subsequently, it suppressed M1 polarization and promoted to the M2 phenotype in LPS-induced BV-2 cells. We first demonstrated that ACT exerted profound transcriptomic impact, which involved regulation of key signaling pathways in inflammation, arginine biosynthesis, as well as pantothenate and CoA biosynthesis, correlating with mitochondria function. ACT treatment reduced microglia M1 polarization by inhibiting the NF-κB signalling pathway. And the metabolic pathways were further confirmed by HPLC-Q-TOF-MS. In addition, ACT rectified excessive ROS to restore mitochondria function through AMPK-mediated PGC-1α and UCP-2 upregulation, consistent with metabolic changes. Intriguingly, ACT may directly bind to both NF-κB and AMPKα, as evidenced by molecular docking. Conclusions: The research provided an infusive mechanism of ACT and illustrated a new perspective based on mitochondrial dysfunction to reveal the connection between metabolism and microglia polarization.