# β-Asarone Mediates the Alleviation of Neuroinflammation in Alzheimer’s Disease Via Modulation of the TREM2/PI3K/AKT Signaling Pathway

## TL;DR

β-asarone reduces neuroinflammation in Alzheimer’s disease by regulating microglial activity through a specific signaling pathway.

## Contribution

This study is the first to show that β-asarone alleviates AD pathology via the TREM2/PI3K/AKT/GSK3β signaling axis.

## Key findings

- β-asarone improved cognitive function and reduced hippocampal damage in 3×Tg-AD mice.
- The compound decreased Aβ deposition and Tau hyperphosphorylation in AD models.
- β-asarone promotes microglial polarization from M1 to M2 phenotypes via TREM2/PI3K/AKT signaling.

## Abstract

Neuroinflammation, driven by dysregulated microglial polarization, is a hallmark of Alzheimer’s disease (AD). Recently, the triggering receptor expressed on myeloid cells 2 (TREM2), a key regulator of microglial function, has emerged as a promising therapeutic target for AD. This study aimed to investigate the therapeutic potential and mechanism of action of the natural compound β-asarone in AD models. Our results demonstrate that β-asarone significantly improved cognitive function, reduced hippocampal neuronal damage, and decreased both Aβ deposition and Tau hyperphosphorylation in 3×Tg-AD mice. Mechanistically, β-asarone upregulated TREM2 expression, activated the PI3K/AKT pathway, and inhibited GSK3β activity, thereby promoting the polarization of microglia from the pro-inflammatory M1 phenotype toward the anti-inflammatory M2 phenotype and alleviating neuroinflammation. This study is the first to elucidate that β-asarone ameliorates AD pathology by modulating microglial polarization via the TREM2/PI3K/AKT/GSK3β signaling axis, providing experimental evidence supporting its potential as an immunomodulatory therapeutic agent for AD.

The online version contains supplementary material available at 10.1007/s10753-025-02435-w.