Dihydromyricetin inhibits microglial activation and neuroinflammation by suppressing <scp>NLRP</scp>3 inflammasome activation in <scp>APP</scp>/<scp>PS</scp>1 transgenic mice

<jats:title>Summary</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Activated microglia‐mediated inflammation plays a key role in the pathogenesis of Alzheimer’s disease (<jats:styled-content style="fixed-case">AD</jats:styled-content>). In addition, chronic activation of <jats:styled-content style="fixed-case">NLRP</jats:styled-content>3 inflammasomes triggered by amyloid β peptide (Aβ) in microglia contributes to persistent neuroinflammation. Here, the primary goal was to assess whether Dihydromyricetin (<jats:styled-content style="fixed-case">DHM</jats:styled-content>), a plant flavonoid compound, is effective therapies for <jats:styled-content style="fixed-case">AD</jats:styled-content>; it is crucial to know whether <jats:styled-content style="fixed-case">DHM</jats:styled-content> will affect microglial activation and neuroinflammation in <jats:styled-content style="fixed-case">APP</jats:styled-content>/<jats:styled-content style="fixed-case">PS</jats:styled-content>1 transgenic mice.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>After <jats:styled-content style="fixed-case">DHM</jats:styled-content> was intraperitoneally injected in <jats:styled-content style="fixed-case">APP</jats:styled-content>/<jats:styled-content style="fixed-case">PS</jats:styled-content>1 double‐transgenic mice, we assessed the effect of <jats:styled-content style="fixed-case">DHM</jats:styled-content> on microglial activation, the expression of <jats:styled-content style="fixed-case">NLRP</jats:styled-content>3 inflammasome components, and the production of inflammatory cytokine <jats:styled-content style="fixed-case">IL</jats:styled-content>‐1β by immunofluorescence and Western blot. To determine whether <jats:styled-content style="fixed-case">DHM</jats:styled-content> play roles in the Aβ production and deposition, amyloid β protein precursor (<jats:styled-content style="fixed-case">APP</jats:styled-content>) and β‐site <jats:styled-content style="fixed-case">APP</jats:styled-content> cleaving enzyme1 (<jats:styled-content style="fixed-case">BACE</jats:styled-content>1), as well as neprilysin (<jats:styled-content style="fixed-case">NEP</jats:styled-content>), were detected by Western blot. Finally, behavior was tested by Morris Water Maze to illustrate whether <jats:styled-content style="fixed-case">DHM</jats:styled-content> treatment has a significantly positive effect on ameliorating the memory and cognition deficits in <jats:styled-content style="fixed-case">AD</jats:styled-content>.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Dihydromyricetin treatment significantly ameliorated memory and cognition deficits and decreased the number of activated microglia in the hippocampus and cortex of <jats:styled-content style="fixed-case">APP</jats:styled-content>/<jats:styled-content style="fixed-case">PS</jats:styled-content>1 mice. In addition, <jats:styled-content style="fixed-case">APP</jats:styled-content>/<jats:styled-content style="fixed-case">PS</jats:styled-content>1 mice show reduced activation of <jats:styled-content style="fixed-case">NLRP</jats:styled-content>3 inflammasomes and reduced expression of <jats:styled-content style="fixed-case">NLRP</jats:styled-content>3 inflammasome components. Furthermore, <jats:styled-content style="fixed-case">DHM</jats:styled-content> could promote clearance of Aβ, a trigger for <jats:styled-content style="fixed-case">NLRP</jats:styled-content>3 inflammasome activation, by increasing levels of <jats:styled-content style="fixed-case">NEP</jats:styled-content> 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.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Taken together, our findings suggest that <jats:styled-content style="fixed-case">DHM</jats:styled-content> prevents progression of <jats:styled-content style="fixed-case">AD</jats:styled-content>‐like pathology through inhibition of <jats:styled-content style="fixed-case">NLRP</jats:styled-content>3 inflammasome‐based microglia‐mediated neuroinflammation and may be a promising therapeutic drug for treating <jats:styled-content style="fixed-case">AD</jats:styled-content>.</jats:p></jats:sec>