A lipopolysaccharide mouse model mirrors neuroinflammatory transcriptional signatures of human Alzheimer’s disease, and the Glucagon‐Like Peptide‐1 receptor agonist semaglutide attenuates neuroinflammation in this model
Authors: Ludwig Mette Q , Belmont‐Rausch Dylan M , Bentsen Marie Aare , Secher Anna , Hansen Stine A Normann , Egerod Kristoffer L , Hansen Charlotte Thim , Dalgaard Kevin D , Merkestein Myrte , Holst Dorte , Pyke Charles , Wichern Franziska , Polex‐Wolf Joseph , Pers Tune H , Knudsen Lotte Bjerre 
Published: December 2022

Background

Neuroinflammation is part of the pathophysiology in Alzheimer’s disease (AD). AD neuroimaging studies highlight increased inflammation, while genome wide association studies indicate that many AD‐associated genes are expressed in glial cells. The hormone and neuropeptide Glucagon‐Like Peptide‐1 (GLP‐1) was originally developed for treatment of type 2 diabetes but has equally important effects in weight loss control and provides cardiovascular benefits. The potential for applying a licensed therapeutic option with a well‐established safety profile is currently being investigated in two phase 3a randomized, placebo‐controlled trials with semaglutide in people with early Alzheimer’s disease (evoke/evoke+). Here, we investigate the molecular effects of semaglutide on lipopolysaccharide (LPS) induced hippocampal neuroinflammation in mice and compare the identified pathways with human gene signatures in AD brain tissue.

Method

Mice were treated daily subcutaneously with semaglutide (30nmol/kg) or vehicle for 28 days, and LPS or vehicle was administered on days 15‐17. RNA‐sequencing and immunohistochemistry was performed to assess transcriptional and morphological changes in the hippocampus at Day 19 and Day 28 (Day 2 and 11 post‐LPS, respectively). RNA‐sequencing analyses included differentially expressed gene analysis, weighted gene co‐regulated network analysis, pathway analysis and gene set enrichment analysis on published human AD datasets.

Result

Semaglutide treatment significantly decreased the area of ionized calcium binding adaptor molecule 1 (Iba1) positive microglia (quantitative assessment) and attenuated co‐expressed inflammatory genes in LPS/semaglutide‐treated mice (p<0.01 vs LPS+vehicle treated mice) on Day 28. Pathway analysis was consistent with an overall dampening of inflammatory processes in mice treated with LPS and semaglutide. The mouse LPS model mirrored the transcriptional signatures identified in people with AD in data of human hippocampal subtype transcriptional signatures, suggesting that semaglutide could potentially alleviate homologous inflammatory molecular processes in humans. A single nucleus RNA‐sequencing study in mice is ongoing to further elucidate the molecular effects of semaglutide on neuroinflammation and will be presented at the conference.

Conclusion

In an LPS‐induced neuroinflammation mouse model, subcutaneously semaglutide reduced hippocampal neuroinflammation as measured by transcriptional changes and microglial area (Iba1). This could be a novel mechanism through which semaglutide, may affect neuronal integrity and function relevant for AD pathophysiology.