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

## TL;DR

Myricetin, a natural compound, reduces Alzheimer's disease symptoms by blocking harmful immune cell activity linked to brain inflammation.

## Contribution

Myricetin is shown to inhibit RORγt-driven Th17 polarization, offering a novel therapeutic strategy for Alzheimer's disease.

## Key findings

- Myricetin suppresses Th17 polarization and IL-17 production by inhibiting RORγt.
- In AD mice, myricetin improves cognition, reduces Aβ plaques, and attenuates microglial activation.
- Myricetin blocks RORγt recruitment to the IL17 promoter, downregulating IL-17 transcription.

## Abstract

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.

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.

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.

Myricetin ameliorates AD pathology by inhibiting RORγt‐driven Th17 polarization, highlighting its potential as a therapeutic agent for AD.

Myricetin inhibits RORγt‐driven Th17 polarization, reducing neuroinflammation and ameliorating cognitive deficits and pathological features in Alzheimer's disease mice, highlighting its potential as a therapeutic agent for AD.