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

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.