• TIIA-pretreated MSCs significantly improve cognitive function and brain glucose metabolism in 3×Tg-AD mice.
• TIIA-MSCs alleviate neuroinflammation by promoting microglial phenotypic switch from pro-inflammatory to neuroprotective states.
• The TREM2/PI3K/Akt signaling pathway is identified as the key mediator of TIIA-MSC anti-inflammatory effects.
• Knockdown of TREM2 abolishes the beneficial effects of TIIA-MSCs, confirming its central role.