Background: Activated microglia-mediated inflammation plays a key role in the pathogenesis of Alzheimer's disease (AD). In addition, chronic activation of NLRP3 inflammasomes triggered by amyloid β peptide (Aβ) in microglia contributes to persistent neuroinflammation. Here, the primary goal was to assess whether Dihydromyricetin (DHM), a plant flavonoid compound, is effective therapies for AD; it is crucial to know whether DHM will affect microglial activation and neuroinflammation in APP/PS1 transgenic mice.
Methods: 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 by immunofluorescence and Western blot. To determine whether DHM play roles in the Aβ production and deposition, amyloid β protein precursor (APP) and β-site APP cleaving enzyme1 (BACE1), as well as neprilysin (NEP), were detected by Western blot. 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: Dihydromyricetin treatment significantly ameliorated memory and cognition deficits and decreased the number of activated microglia in the hippocampus and cortex of APP/PS1 mice. In addition, APP/PS1 mice show reduced activation of NLRP3 inflammasomes and reduced expression of NLRP3 inflammasome components. 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.
Keywords: Alzheimer’s disease; NLRP3 inflammasome; dihydromyricetin; microglia.
© 2018 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.