Myricetin Suppresses Inflammatory Th17 Polarization to Mitigate Alzheimer's Disease Pathogenesis.

AIMS: This study aimed to investigate the therapeutic potential of myricetin, a natural flavonoid, in Alzheimer's disease (AD) by targeting Th17 cell-mediated neuroinflammation through inhibition of the transcription factor RORγt. METHODS: Virtual screening of 47,963 compounds identified myricetin as a potential RORγt inhibitor, validated by molecular docking and dynamics simulations. In vivo, 3xTg-AD mice were treated with myricetin (50 mg/kg/day) for 8.5 weeks, followed by behavioral tests (novel object recognition, Morris water maze) and pathological analyses (HE/Nissl staining, immunohistochemistry, Western blot). In vitro, Th17 polarization assays and mechanistic studies (ChIP, EMSA, MST) were performed to elucidate myricetin's action on RORγt-IL-17 signaling. RESULTS: Myricetin exhibited stable binding to RORγt (Kd = 6.40 μM), suppressing Th17 polarization and IL-17 production. In AD mice, myricetin improved cognitive function, reduced neuronal damage, decreased Aβ plaques and phosphorylated tau levels, and attenuated microglial activation. Mechanistically, myricetin blocked RORγt recruitment to the IL17 promoter, downregulating IL-17 transcription. CONCLUSION: Myricetin ameliorates AD pathology by inhibiting RORγt-driven Th17 polarization, highlighting its potential as a therapeutic agent for AD.