Semaglutide attenuates neuroinflammation in male mice by preventing neutrophil infiltration and suppressing multi-cellular transcriptional signatures

Neurodegenerative disorders like Alzheimer's disease (AD) are characterized by progressive cognitive decline, with neuroinflammation increasingly recognized as a key driver. Current treatments for AD primarily manage symptoms and do not halt disease progression, highlighting an urgent need for novel therapeutic strategies. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated neuroprotective potential in preclinical models, but the precise cellular and molecular mechanisms by which they modulate neuroinflammation remain largely undefined. Understanding these pathways could unlock new therapeutic avenues for neurodegenerative conditions.

Researchers utilized a mouse model of lipopolysaccharide (LPS)-induced neuroinflammation in male mice to investigate the effects of semaglutide. The study aimed to elucidate how semaglutide coordinates cellular responses to resolve neuroinflammation. Key endpoints included assessing brain infiltration of neutrophils, measuring cytokine release, and analyzing neuroinflammation-associated transcriptional signatures in specific brain cell types. The study focused on identifying cellular mechanisms underlying GLP-1RA effects on neuroinflammation, particularly in microglia, endothelial cells, and pericytes.

Semaglutide treatment in male mice effectively prevented the brain infiltration of neutrophils, a critical component of acute inflammatory responses. It also suppressed excessive cytokine release, indicating a broad anti-inflammatory effect. Furthermore, the study identified that semaglutide specifically suppressed neuroinflammation-associated transcriptional signatures in microglia, endothelial cells, and a subset of pericytes, highlighting a multi-cellular coordinated response. Mechanistically, a subset of Glp1r-expressing neurons located in the dorsal vagal complex was identified; these neurons, upon semaglutide treatment, regulated genes involved in anti-inflammatory signaling. This suggests a neural circuit-mediated component to the observed anti-inflammatory effects. Importantly, the semaglutide-modulated pathways showed significant overlap with inflammatory signatures found in human neurodegenerative diseases, including Alzheimer's disease. This finding suggests the broad relevance of GLP-1R signaling for conditions characterized by neuroinflammation. The coordinated multi-cellular programs orchestrated by GLP-1R signaling appear crucial for resolving neuroinflammation.

Semaglutide orchestrates resolution of neuroinflammation through coordinated multi-cellular programs, specifically suppressing inflammatory transcriptional signatures in microglia, endothelial cells, and pericytes, and activating anti-inflammatory signaling via Glp1r-expressing neurons in the dorsal vagal complex.