Semaglutide treatment reverses HFD induced hippocampal microglia activation and improves cognitive dysfunction.

Tissue & cell2026PMID: 41916100

View on PubMed DOI: 10.1016/j.tice.2026.103495

Plain Language Summary

Demonstrates semaglutide reverses high-fat diet-induced hippocampal microglia activation and improves cognitive function in C57BL/6 mice via IGFBPL-1 and PI3K/AKT pathway restoration. Semaglutide treatment reduced phospho-Tau, amyloid-β, and neuroinflammation markers while improving memory performance. IGFBPL-1—a neuroprotective factor suppressed by HFD—mediated semaglutide's cognitive benefits. Establishes a neuroprotective mechanism for semaglutide in obesity-associated neuroinflammation—directly relevant to semaglutide's ongoing trials for Alzheimer's disease and other neurodegenerative conditions.

Abstract

Long-term high-fat diets (HFD) induce obesity, neuroinflammation, and cognitive decline, increasing Alzheimer's disease (AD) risk. This study explores whether Semaglutide, a GLP-1 receptor agonist, mitigates these effects by modulating microglia via IGFBPL-1 and the PI3K/AKT pathway. In HFD-fed C57/BL6 mice, Semaglutide improved cognitive function, reduced hippocampal microglia activation, and decreased AD-like pathology (phospho-Tau, Aβ). IGFBPL-1, a neuroprotective factor downregulated by HFD and restored by Semaglutide. Direct IGFBPL-1 supplementation replicated Semaglutide's benefits, while PI3K/AKT inhibition blocked them. These findings reveal IGFBPL-1 as a key mediator of Semaglutide's neuroprotection, offering novel insights into combating obesity-linked neurodegeneration.

Authors

Gong, Haodong; Liu, Junlu; Wang, Yihan; Lin, Xufan; Wu, Guangsen; Ou, Yichao; Zhou, Mingfeng; Yang, le; Peng, Junxiang; Ye, Xinyun; Wang, Yongjia; Xu, Fei; Zhou, Hongzhen; Feng, Zhanpeng

Keywords

Alzheimer's diseaseIGFBPL-1MicrogliaNeural inflammationNeurodegenerationSemaglutide