Kevin D. Dalgaard, Denmark
Novo Nordisk Global Drug DiscoveryAuthor Of 1 Presentation
THE GLP-1 RECEPTOR AGONIST SEMAGLUTIDE REDUCES NEUROINFLAMMATION IN A LIPOPOLYSACCHARIDE MOUSE MODEL
Abstract
Aims
Neuroinflammation is part of the pathophysiology in numerous neurodegenerative diseases including Alzheimer’s disease (AD). AD neuroimaging studies highlight increased inflammation markers, while GWAS studies indicate that many AD-associated genes are expressed in glial cells. The hormone and neurotransmitter Glucagon-Like Peptide-1 (GLP-1) was originally developed for treatment of type 2 diabetes but have pleiotropic effects. GLP-1 receptor agonists (GLP-1RAs) also reduce cardiovascular disease, highlighting reduced inflammation as a benefit of GLP-1RAs. Small clinical studies have indicated that GLP-1RAs may have clinical relevance in AD and PD. Here, we investigated the effects of the GLP-1RA semaglutide on lipopolysaccharide (LPS) induced hippocampal neuroinflammation in mice as a model of early AD pathophysiology.
Methods
Mice were treated with semaglutide or vehicle for 28 days, and LPS or vehicle was administered on days 15-17. Quantitative assessment of the microglial-specific marker Iba1 (ionized calcium binding adaptor molecule 1) was performed to measure the area of microglia in the hippocampus at Day 19 and Day 28.
Results
LPS significantly increased hippocampal Iba1 area on Day 19 in mice dosed with LPS/vehicle compared to vehicle/vehicle controls (p<0.001). On Day 28, LPS/vehicle-treated mice continued to have a significantly higher area of hippocampal Iba1 (p<0.05 vs vehicle/vehicle controls), whereas semaglutide treatment significantly reduced Iba1 area in LPS/semaglutide-treated mice (p<0.01 vs LPS + vehicle treated mice); Figure 1.
Conclusions
In an LPS-induced neuroinflammation model, semaglutide reduced hippocampal neuroinflammation as measured by microglial area (Iba1). This could be a novel mechanism through which semaglutide may affect neuronal integrity and function relevant for AD pathophysiology.