The Anti-inflammatory Efficacy Of Dihydromyricetin In APP/PS1 Transgenic Mice And Its Mechanisms

Objective: To observe the effect of dihydromyricetin(DHM)on activated microglia-mediated inflammation in APP/PS1 double transgenicmice.And discussing its underlying mechanisms in-depth.Methods: In this study,BV2 cells and APP/PS1 double transgenic mice were employed.32 mice(4-month-old)were randomly divided into DHM groups and control groups.The mice of DHM groups were intraperitonealy injected with DHM 1mg/(kg·d)and the same amount of DMSO dilution were injected in control group for 2 weeks and 4 weeks.After DHM was intraperitoneally injected in APP/PS1 double transgenic mice,we assessed the effect of DHM on microglial activation,the expression of NLRP3 inflammasome components and the production of inflammatory cytokine IL-1β and TNFα by immunofluorescence and western blot.To determine whether DHM play roles in the Aβ production and deposition,APP and BACE1,as well as neprilysin(NEP)were detected by western blot,while M1 and M2 phenotypes of microglia were detected by the immunofluorescence staining and Western blotting.Finally,behavior was tested by Morris Water Maze to illustrate whether DHM treatment has a significantly positive effect on ameliorating the memory and cognition deficits in AD.Results: DHM treatment significantly ameliorated memory and cognition deficits and decreased the number of activated microglia in the hippocampus and cortex of APP/PS1 mice.At the same time,APP/PS1 mice show reduced activation of NLRP3 inflammasomes and reduced expression of NLRP3 inflammasome components.In vitro,compared with control groups,DHM treatment could significantly reduce the expression levels of TNFa,as well as inhibit the expression of nitric oxide synthase(iNOS)and up-regulate arginase-1(Arg-1).Furthermore,DHM could promote clearance of Aβ,a trigger for NLRP3 inflammasome activation,by increasing levels of NEP and shift microglial conversion to the M2-specific agrinase-1-positive cell phenotype,which enhances microglial clearance of Aβ and its aggregates but not production of Aβ.Conclusion: Taken together,our findings suggest that DHM prevents progression of AD-like pathology through inhibition of NLRP3 inflammasome-based microglia-mediated neuroinflammation and may be a promising therapeutic drug for treating AD.