Honokiol Restores Microglial Phagocytosis By Reversing Metabolic Reprogramming

Background: Dysfunction of microglia has been increasingly recognized as a causative factor in Alzheimer's disease (AD); thus, developing medicines capable of restoring microglial functions is critically important and constitutes a promising therapeutic strategy. Honokiol is a natural neuroprotective compound extracted from Magnolia officinalis, which may play roles in AD therapy.Objective: This study aimed to evaluate the role and the underlying mechanisms of honokiol in microglial phagocytosis.Methods: MTT and flow cytometry were used to assess the cell viability and apoptosis, respectively. Phagocytic capacity, mitochondrial reactive oxygen species production, and membrane potential were evaluated using fluorescence microscopy. Seahorse XF24 extracellular flux analyzer was for cell glycolysis and oxidative phosphorylation detection. Mass spectrometry was applied for metabolites measurement. Quantitative real-time polymerase chain reaction and western blotting were performed to detect the mRNA and protein level of PPAR gamma and PGC1 alpha, respectively.Results: Honokiol alleviated A beta(42)-induced BV2 neurotoxicity. Honokiol promoted phagocytic efficiency of BV2 cells through reversing a metabolic switch from oxidative phosphorylation to anaerobic glycolysis and enhancing ATP production. Meanwhile, honokiol reduced mitochondrial reactive oxygen species production and elevated mitochondrial membrane potential. Moreover, honokiol increased the expression of PPAR gamma and PGC1 alpha, which might play positive roles in energy metabolism and microglial phagocytosis.Conclusion: In this study, honokiol was identified as an effect natural product capable of enhancing mitochondrial function thus promoting microglial phagocytic function.