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Abstract Details

A Lipopolysaccharide Mouse Model Mirrors Neuroinflammatory Transcriptional Signatures of Human AD, and the Glucagon-Like Peptide-1 Receptor Agonist Semaglutide Attenuates Neuroinflammation in this Model
Aging, Dementia, Cognitive, and Behavioral Neurology
P1 - Poster Session 1 (8:00 AM-9:00 AM)
7-007
Neuroinflammation is part of the pathophysiology in AD. AD neuroimaging studies highlight increased inflammation, while genome wide association studies indicate that many AD-associated genes are expressed in glial cells. The glucagon-like peptide-1 receptor agonist semaglutide is currently being investigated in two phase 3a randomized, placebo-controlled trials in people with early Alzheimer’s disease (evoke/evoke+).
We aimed to investigate the molecular effects of semaglutide on lipopolysaccharide (LPS) induced hippocampal neuroinflammation in mice and further to compare human gene expression signatures in Alzheimer’s disease (AD) brain tissue with those induced by LPS.
Mice were treated daily with subcutaneous semaglutide (30nmol/kg) or vehicle for 28 days, and LPS or vehicle was administered on days 15-17. RNA-sequencing and immunohistochemistry were 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.
Semaglutide treatment significantly decreased the area of ionized calcium binding adaptor molecule 1 (Iba1) positive microglia (quantitative assessment) and attenuated co-expressed inflammatory genes vs vehicle in LPS-treated mice (p<0.01) 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.
In an LPS-induced neuroinflammation mouse model, semaglutide reduced hippocampal neuroinflammation as measured by transcriptional changes and microglial area (Iba1). This could represent a novel mechanism whereby semaglutide may affect neuronal integrity and function, and thereby AD pathophysiology.
Authors/Disclosures
Christian Wichmann (Novo Nordisk A/S)
PRESENTER
Dr. Wichmann has received personal compensation for serving as an employee of Novo Nordisk.
Mette Ludwig, PhD (Novo Nordisk Foundation Center for Basic Metabolic Research) Dr. Ludwig has nothing to disclose.
Dylan Rausch, PhD Dr. Rausch has nothing to disclose.
Anna Secher, PhD (Novo Nordisk) Dr. Secher has received personal compensation for serving as an employee of Novo Nordisk. An immediate family member of Dr. Secher has received personal compensation for serving as an employee of Novo Nordisk. Dr. Secher has stock in Novo Nordisk.
Marie Aare Bentsen, PhD (Novo Nordisk) Dr. Bentsen has received personal compensation for serving as an employee of Novo Nordisk. An immediate family member of Dr. Bentsen has stock in Novo Nordisk.
Stine Normann Hansen, PhD Dr. Hansen has received personal compensation for serving as an employee of Neumirna Therapeutics. Dr. Hansen has received intellectual property interests from a discovery or technology relating to health care.
Anne-Mette Bjerregaard, PhD (Novo Nordisk A/S) Dr. Bjerregaard has received personal compensation for serving as an employee of Novo Nordisk A/S.
Kristoffer Niss, PhD (Novo Nordisk) Dr. Niss has nothing to disclose.
Kristoffer L. Egerod No disclosure on file
Charlotte Thim Hansen, MD (Novo Nordisk A/S) Dr. Hansen has received personal compensation for serving as an employee of Novo Nordisk A/S. Dr. Hansen has stock in Novo Nordisk A/S.
Kevin Dalgaard, PhD (Lundbeckfonden BioCapital) Dr. Dalgaard has received personal compensation for serving as an employee of Novo Nordisk.
Myrte Merkestein, PhD (Novo Nordisk A/S) Dr. Merkestein has received personal compensation for serving as an employee of Novo Nordisk A/S.
Dorte Holst No disclosure on file
Charles Pyke No disclosure on file
Franziska Wichern (Gubra A/S) Mrs. Wichern has received personal compensation for serving as an employee of Gubra ApS.
Joseph Polex-Wolf, PhD (Novo Nordisk A/S) Dr. Polex-Wolf has received personal compensation for serving as an employee of Novo Nordisk A/S.
Tune H. Pers No disclosure on file
Lotte B. Knudsen No disclosure on file