Dihydromyricetin inhibits microglial activation and neuroinflammation by suppressing NLRP3 inflammasome activation in APP/PS1 transgenic mice.

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. 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. 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. 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.

Feng J ，Wang JX ，Du YH ，Liu Y ，Zhang W ，Chen JF ，Liu YJ ，Zheng M ，Wang KJ ，He GQ ... -  《-》

Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice.

Dempsey C ，Rubio Araiz A ，Bryson KJ ，Finucane O ，Larkin C ，Mills EL ，Robertson AAB ，Cooper MA ，O'Neill LAJ ，Lynch MA ... -  《-》

TLR4/Rac1/NLRP3 Pathway Mediates Amyloid-β-Induced Neuroinflammation in Alzheimer's Disease.

Zhu M ，Liu Y ，Chen C ，Chen H ，Ni W ，Song Y ，Lv B ，Hua F ，Cui G ，Zhang Z ... -  《-》

Urolithin A attenuates memory impairment and neuroinflammation in APP/PS1 mice.

Gong Z ，Huang J ，Xu B ，Ou Z ，Zhang L ，Lin X ，Ye X ，Kong X ，Long D ，Sun X ，He X ，Xu L ，Li Q ，Xuan A ... -  《Journal of Neuroinflammation》

Lychee seed polyphenol inhibits Aβ-induced activation of NLRP3 inflammasome via the LRP1/AMPK mediated autophagy induction.

Emerging evidence indicates that the enhancement of microglial autophagy inhibits the NLRP3 inflammasome mediated neuroinflammation in Alzheimer's disease (AD). Meanwhile, low density lipoprotein receptor-related protein 1 (LRP1) highly expressed in microglia is able to negatively regulate neuroinflammation and positively regulate autophagy. In addition, we have previously reported that an active lychee seed fraction enriching polyphenol (LSP) exhibits anti-neuroinflammation in Aβ-induced BV-2 cells. However, its molecular mechanism of action is still unclear. In this study, we aim to investigate whether LSP inhibits the NLRP3 inflammasome mediated neuroinflammation and clarify its molecular mechanism in Aβ-induced BV-2 cells and APP/PS1 mice. The results showed that LSP dose- and time-dependently activated autophagy by increasing the expression of Beclin 1 and LC3II in BV-2 cells, which was regulated by the upregulation of LRP1 and its mediated AMPK signaling pathway. In addition, both the Western blotting and fluorescence microscopic results demonstrated that LSP could significantly suppress the activation of NLRP3 inflammasome by inhibiting the expression of NLRP3, ASC, the cleavage of caspase-1, and the release of IL-1β in Aβ(1-42)-induced BV-2 cells. In addition, the siRNA LRP1 successfully abolished the effect of LSP on the activation of AMPK and its mediated autophagy, as well as the inhibition of NLRP3 inflammasome. Furthermore, LSP rescued PC-12 cells which were induced by the conditioned medium from Aβ(1-42)-treated BV-2 cells. Moreover, LSP improved the cognitive function and inhibited the NLRP3 inflammasome in APP/PS1 mice. Taken together, LSP inhibited the NLRP3 inflammasome-mediated neuroinflammation in the in vitro and in vivo models of AD, which was closely associated with the LRP1/AMPK-mediated autophagy. Thus, the findings from this study further provide evidences for LSP serving as a potential drug for the treatment of AD in the future.

Qiu WQ ，Pan R ，Tang Y ，Zhou XG ，Wu JM ，Yu L ，Law BY ，Ai W ，Yu CL ，Qin DL ，Wu AG ... -  《-》