Neuromolecular medicineAug 20, 2026

Semaglutide may reduce inflammation-related memory problems by modifying key cell signaling proteins

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 21, 2026

Abstract

Semaglutide significantly rescued LPS-induced cognitive deficits in a mouse model of neurocognitive impairment.

Perioperative neurocognitive disorder may progress due to high-risk factors like advanced age, obesity, diabetes, and preoperative neurological dysfunction.
Neuroinflammation is identified as a key mechanism in the development of perioperative neurocognitive disorder.
In a mouse model, LPS injection led to cognitive impairment and disruptions in the AKT-mTOR signaling pathway.
Semaglutide treatment improved cognitive function and restored O-GlcNAcylation levels in the hippocampus.
The effects of semaglutide include activation of the AKT-mTOR pathway, restoration of synaptic GABA receptor localization, and attenuation of neuronal damage.

Simplified

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.

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Semaglutide may reduce inflammation-related memory problems by modifying key cell signaling proteins

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