Tanshinone IIA-pretreated mesenchymal stem cells alleviate neuroinflammation in 3×Tg-AD mice via the TREM2/PI3K/Akt pathway

Abstract

Neuroinflammation is a key pathogenic factor for neurodegenerative diseases. Mesenchymal stem cell (MSC) transplantation, as a potential strategy for regulating neuroinflammation, has received extensive attention. Our previous research revealed that compared with ordinary MSC, MSC pretreated with tanshinone IIA (TIIA), referred to as TIIA-MSC, exhibited superior anti-neuroinflammatory activity, but the mechanism of action remains unclear. To clarify the underlying mechanism, this study integrated in vitro and in vivo experiments and evaluated the therapeutic effect of TIIA-MSC in a triple-transgenic Alzheimer’s disease mouse model (3×Tg-AD mice) and explored its mechanism of action in a lipopolysaccharide (LPS)-induced BV2 microglial cell inflammation model. The results showed that TIIA-MSC could significantly improve the cognitive function of 3×Tg-AD mice, increase brain glucose metabolism levels, promote the recovery of synaptic and mitochondrial structures, and effectively alleviate neuroinflammatory responses. In vitro experiments further verified the superior inhibitory effect of TIIA-MSC on microglial cell activation and proinflammatory factor release. Mechanistic studies have indicated that the triggering receptor expressed on myeloid cells 2 (TREM2) is the key molecule that mediates this process. The knockdown of TREM2 expression significantly weakened the anti-inflammatory effect of TIIA-MSC, suggesting that TREM2 plays a central role in this process. Further analysis revealed that by activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway downstream of TREM2, TIIA-MSC may promote the transformation of the functional state of microglia from mainly proinflammatory to having neuroprotective and repair properties. This study systematically revealed the molecular mechanism by which TIIA-MSC regulate microglial cell phenotypic transformation through the TREM2/PI3K/Akt pathway and exert anti-neuroinflammatory effects, providing new ideas and an experimental basis for expanding the application of MSC in the treatment of neurodegenerative diseases.

1. Introduction

Neuroinflammation is a core link in the onset and progression of neurodegenerative diseases, especially Alzheimer’s disease (AD) [1, 2], for which therapeutic options remain limited [3, 4]. In recent years, stem cell therapy based on mesenchymal stem cells (MSC), owing to their unique immune regulation and neuroprotective functions, has become important for alleviating neuroinflammation and treating diseases such as AD [5, 6]. MSC not only possess multidirectional differentiation potential and the ability to migrate directionally to the injury site [7] but also secrete various neurotrophic factors and exhibit significant anti-oxidant and anti-inflammatory activities [8]. These characteristics together establish the dominant role of MSC in the field of stem cell therapy [9].

Although stem cell therapy has great therapeutic potential, its clinical application still faces key challenges, such as insufficient targeting and a low survival rate after transplantation, which severely limit its overall efficacy [10, 11]. To overcome these bottlenecks, researchers have developed various pretreatment [12, 13] and engineering strategies [14, 15], aiming to increase the survival, directed migration and proliferation differentiation ability of stem cells, promote their efficient homing to diseased tissues, and effectively stimulate the secretion of neurotrophic factors, thereby more strongly promoting the recovery of neural function [16, 17].