The GLP-1 receptor agonist, liraglutide, fails to slow disease progression in SOD1G93A and TDP-43Q331K transgenic mouse models of ALS

Amy Keerie,Christian Holscher,Isaac Kirkland,Andrew Grierson,James J P Alix,Heledd Brown-Wright,Richard J Mead

doi:10.1038/s41598-021-96418-0

Abstract

GLP-1 receptor agonists used for the treatment of diabetes, have shown some neuroprotective effects in cellular and animal models of Alzheimer’s disease (AD) and Parkinson’s disease (PD). There are currently few studies investigating GLP-1 receptor agonists in the treatment of ALS, where these neuroprotective effects may be beneficial. Here we investigate the effects of liraglutide, a GLP-1 receptor agonist, in two well characterised transgenic mouse models of ALS (SOD1G93A and TDP-43Q331K) to determine if liraglutide could be a potential treatment in ALS patients. Doses of liraglutide previously shown to have efficacy in AD and PD mouse models were used. Behavioural testing was carried out to ascertain the effect of liraglutide on disease progression. Immunohistochemical analysis of tissue was used to determine any neuroprotective effects on the CNS. We found that liraglutide dosed animals showed no significant differences in disease progression when compared to vehicle dosed animals in either the SOD1G93A or TDP-43Q331K mouse models of ALS. We also observed no changes in motor neuron counts or glial activation in lumbar spinal cords of liraglutide treated mice compared to vehicle dosed mice. Overall, we found no evidence to support clinical evaluation of liraglutide as a potential candidate for the treatment of ALS.

Highlights

Glucagon Like Peptide 1 (GLP-1) receptor agonists used for the treatment of diabetes, have shown some neuroprotective effects in cellular and animal models of Alzheimer’s disease (AD) and Parkinson’s disease (PD)
We investigated the effect of liraglutide, a GLP-1 receptor agonist, in two mouse models which recapitulate some features of Amyotrophic lateral sclerosis (ALS) pathophysiology and found no evidence that disease progression was altered at the behavioural or pathological level
The TDP-43Q331K mouse model used in this study may be more representative of ALS patients and shows signs of having an FTD-like phenotype with remarkable similarities to a more physiological knock-in model[25]

Summary

Introduction

GLP-1 receptor agonists used for the treatment of diabetes, have shown some neuroprotective effects in cellular and animal models of Alzheimer’s disease (AD) and Parkinson’s disease (PD). There is increasing evidence that Glucagon Like Peptide 1 (GLP-1) Receptor agonists have therapeutic potential in neurodegenerative diseases These agents were developed for the treatment of diabetes mellitus but several trials are underway in both Parkinson’s disease (PD) and Alzheimer’s disease (AD). We set out to evaluate this clinically approved, CNS penetrating therapeutic in two mouse models of Amyotrophic lateral sclerosis (ALS) If positive, this data could directly support a clinical trial with liraglutide in ALS. It is worth noting that a trial of the anti-diabetic agent pioglitazone (PPARγ agonist) in ALS with the rationale of attenuating inflammation, failed to show any b enefit[9] This was based on two preclinical efficacy studies in the SOD1G93A mouse which did not account for the well described pitfalls in experimental design[10], which have led to new guidelines for preclinical research. The use of different model systems increases the confidence in translation from mouse to human studies

Methods

Results

Conclusion