Animal Models of Multiple Sclerosis: Can They Advance Future Therapies?

Editorial

13 June 2023

Editorial: Animal models of multiple sclerosis: can they advance future therapies?

Tara Maria DeSilva

and

Olaf Stuve

4,446 views

0 citations

Editors

Tara Maria DeSilva

Cleveland Clinic Lerner College of Medicine, School of Medicine, Case Western Reserve University

Olaf Stuve

University of Texas Southwestern Medical Center

Impact

Remyelination assessment in mouse models. (A) Myelin sheath visualization by electron microscopy with thinner myelin sheaths in remyelinated axons (A1) in EAE compared to naïve spinal cord. (B) In vivo two photon microscopy through cranial windows over the somatosensory cortex of Mobp-EGFP mice allows for visualization of loss and replacement of oligodendrocytes and myelin sheaths. (C) Lineage tracing approach to visualize myelin sheaths from newly born oligodendrocytes utilizing Cspg4-CreER™; Mapt-mGFP mice and tamoxifen injection prior to EAE induction. New myelin sheaths generated by OPCs express mGFP reporter (green) and wrap neurofilament positive axons (red). (D) Electron microscopy of conditional knockout of muscarinic acetylcholine receptor Chrm1 in oligodendrocytes (Chrm1 cKO: Cnp-Cre+; Chrm1fl/fl) in EAE results in reduced axonal loss and enhanced remyelination in spinal cord indicated by significantly increased axons with g-ratios >0.8. Black bars indicate Chrm1 cKO and white bars Cnp-Cre-; Chrm1fl/fl control. A1-remyelinated axon, A2-demyelinated axon. (E) Longitudinal visual evoked potential (VEP) waveforms during and off cuprizone (CPZ) diet. N1 latency is prolonged on cuprizone diet and recovers after return to normal diet. Black lines-healthy/normal diet mice, gray lines-cuprizone treated mice. (A,C,D) Reproduced from Mei et al. (2016a), accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery, eLife © Creative Commons. (B) Reproduced from Orthmann-Murphy et al. (2020), remyelination alters the pattern of myelin in the cerebral cortex, eLife © Creative Commons. (E) Reproduced from Marenna et al. (2022), visual evoked potentials to monitor myelin cuprizone-induced functional changes, Frontiers in Neuroscience © Creative Commons.

Review

28 June 2023

Remyelination in animal models of multiple sclerosis: finding the elusive grail of regeneration

Davin Packer

, 1 more and

Em P. Harrington

5,783 views

5 citations

Review

12 April 2023

The cerebrospinal fluid immune cell landscape in animal models of multiple sclerosis

Gregory F. Wu

3,321 views

1 citations

Mini Review

29 March 2023

Utility of the visual system to monitor neurodegeneration in multiple sclerosis

Gabrielle M. Mey

and

Tara M. DeSilva

2,204 views

4 citations

Schematic overview of inflammatory demyelination models, showing how inflammation contributes to de- and re-myelination following cuprizone intoxication. ATCup, Adoptive Transfer Cuprizone; CAE, Cuprizone Autoimmune Encephalitis; CFA, Complete Freund’s Adjuvant; DOX, Doxycyclin; EAE, Experimental Autoimmune Encephalomyelitis; MOG, Myelin oligodendrocyte glycoprotein; OPC, Oligodendrocyte precursor cells; PTX, Pertussis toxin.

Mini Review

03 November 2022

Animal models to investigate the effects of inflammation on remyelination in multiple sclerosis

Marjan Gharagozloo

, 1 more and

Peter A. Calabresi

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS). In people with MS, impaired remyelination and axonal loss lead to debilitating long-term neurologic deficits. Current MS disease-modifying drugs mainly target peripheral immune cells and have demonstrated little efficacy for neuroprotection or promoting repair. To elucidate the pathological mechanisms and test therapeutic interventions, multiple animal models have been developed to recapitulate specific aspects of MS pathology, particularly the acute inflammatory stage. However, there are few animal models that facilitate the study of remyelination in the presence of inflammation, and none fully replicate the biology of chronic demyelination in MS. In this review, we describe the animal models that have provided insight into the mechanisms underlying demyelination, myelin repair, and potential therapeutic targets for remyelination. We highlight the limitations of studying remyelination in toxin-based demyelination models and discuss the combinatorial models that recapitulate the inflammatory microenvironment, which is now recognized to be a major inhibitor of remyelination mechanisms. These models may be useful in identifying novel therapeutics that promote CNS remyelination in inflammatory diseases such as MS.

5,300 views

19 citations

A myriad of experimental autoimmune encephalomyelitis (EAE) models have been developed to capture varied aspects of the clinical course of multiple sclerosis (MS) [C57BL/6 (B6), SJL/J, and PL/J mice]. Genetic models have allowed the study of T and B cells in MS in TCR and B-cell receptor (BCR) transgenics. Germ-free models have enabled the study of the gut microbiome. Viral models, such as Theiler’s murine encephalomyelitis virus (TMEV), have elucidated viral contribution to MS. MS-related demyelination and remyelination has been studied in cuprizone and lysolecithin models. Connexin knockouts have been used to study the role of the blood brain barrier (BBB) in neuroinflammation. Central tolerance has been examined in shiverer transgenic mice.

Review

04 November 2022

Advantages and limitations of experimental autoimmune encephalomyelitis in breaking down the role of the gut microbiome in multiple sclerosis

Esther Melamed

, 1 more and

Cara Fonken

6,332 views

9 citations

Review

19 October 2022

Chronic experimental autoimmune encephalomyelitis is an excellent model to study neuroaxonal degeneration in multiple sclerosis

Rhonda R. Voskuhl

and

Allan MacKenzie-Graham

Animal models of multiple sclerosis (MS), specifically experimental autoimmune encephalomyelitis (EAE), have been used extensively to develop anti-inflammatory treatments. However, the similarity between MS and one particular EAE model does not end at inflammation. MS and chronic EAE induced in C57BL/6 mice using myelin oligodendrocyte glycoprotein (MOG) peptide 35–55 share many neuropathologies. Beyond both having white matter lesions in spinal cord, both also have widespread neuropathology in the cerebral cortex, hippocampus, thalamus, striatum, cerebellum, and retina/optic nerve. In this review, we compare neuropathologies in each of these structures in MS with chronic EAE in C57BL/6 mice, and find evidence that this EAE model is well suited to study neuroaxonal degeneration in MS.

10,234 views

21 citations

Review

13 October 2022

Theiler’s virus-induced demyelinating disease as an infectious model of progressive multiple sclerosis

Steven C. Pike

, 2 more and

Francesca Gilli

Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease of unknown etiology. However, several studies suggest that infectious agents, e.g., Human Herpes Viruses (HHV), may be involved in triggering the disease. Molecular mimicry, bystander effect, and epitope spreading are three mechanisms that can initiate immunoreactivity leading to CNS autoimmunity in MS. Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD) is a pre-clinical model of MS in which intracerebral inoculation of TMEV results in a CNS autoimmune disease that causes demyelination, neuroaxonal damage, and progressive clinical disability. Given the spectra of different murine models used to study MS, this review highlights why TMEV-IDD represents a valuable tool for testing the viral hypotheses of MS. We initially describe how the main mechanisms of CNS autoimmunity have been identified across both MS and TMEV-IDD etiology. Next, we discuss how adaptive, innate, and CNS resident immune cells contribute to TMEV-IDD immunopathology and how this relates to MS. Lastly, we highlight the sexual dimorphism observed in TMEV-IDD and MS and how this may be tied to sexually dimorphic responses to viral infections. In summary, TMEV-IDD is an underutilized murine model that recapitulates many unique aspects of MS; as we learn more about the nature of viral infections in MS, TMEV-IDD will be critical in testing the future therapeutics that aim to intervene with disease onset and progression.

4,306 views

12 citations