• TIIA-pretreated MSCs significantly improve cognitive function and brain glucose metabolism in 3×Tg-AD mice, while promoting synaptic and mitochondrial recovery.
• TIIA-MSCs exert superior anti-neuroinflammatory effects by inhibiting microglial activation and proinflammatory cytokine release in vitro.
• The TREM2 receptor is a critical mediator of TIIA-MSC's anti-inflammatory action, as its knockdown abolishes the therapeutic benefit.
• Mechanistically, TIIA-MSCs activate the TREM2/PI3K/Akt pathway to shift microglia from a proinflammatory to a neuroprotective phenotype, offering a novel therapeutic strategy for AD.