Semaglutide Alleviates LPS-Induced Cognitive Disorder via O-GlcNAcylation of AKT-mTOR Signaling Pathway Components.

Perioperative neurocognitive disorder (PND) manifests as neurocognitive alterations induced by anesthesia and surgical stress. High-risk factors, including advanced age, obesity, diabetes, and preoperative neurological dysfunction, accelerate PND progression, with neuroinflammation serving as a core pathological mechanism throughout PND pathogenesis. Semaglutide regulates neuroinflammation in patients with diabetes and stroke, yet its role in PND remains undefined.A lipopolysaccharide (LPS)-induced inflammatory neurocognitive impairment mouse model was established via intracerebroventricular injection. Mice were treated with semaglutide alone or combined with the O-GlcNAc transferase inhibitor OSMI-1 and AKT-silencing adeno-associated viruses. Behavioral, biochemical and immunofluorescence assays were performed to evaluate cognitive function and molecular changes. Semaglutide significantly rescued LPS-induced cognitive deficits and restored hippocampal O-GlcNAcylation. Mechanistically, LPS inhibited AKT O-GlcNAc modification and AKT-mTOR pathway activity, facilitated mTOR-gephyrin binding, disrupted GABAAR distribution, aggravated neuronal apoptosis, and impaired synaptic plasticity. Semaglutide reversed these abnormalities by elevating AKT O-GlcNAcylation to activate the AKT-mTOR pathway, which triggered mTOR-gephyrin dissociation, restored synaptic GABAAR localization, attenuated neuronal damage, and rescued synaptic plasticity.Semaglutide ameliorates PND via AKT O-GlcNAcylation-mediated AKT-mTOR activation and subsequent neuroprotective effects.