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Repurposing niclosamide in mouse models of amyotrophic lateral sclerosis

ABSTRACT: ALS is a complex neurodegenerative disease influenced by genetic, epigenetic, and environmental factors, resulting in dysfunction in cellular and molecular pathways. The limited efficacy of current treatments highlights the need for combination therapies targeting multiple aspects of the disease. Niclosamide, an anthelminthic drug listed as an essential medicine, has been repurposed in clinical trials due to its anti-inflammatory and anti-fibrotic properties. Niclosamide can inhibit various molecular pathways (such as STAT3 and mTOR) that are dysregulated in ALS, suggesting its potential to disrupt these altered mechanisms associated with the pathology. Our recent findings have demonstrated that niclosamide can effectively inhibit inflammatory and fibrotic molecular pathways in ALS models. We administered niclosamide intraperitoneally to two transgenic murine models, FUS and SOD1-G93A mice, which replicate key pathologies and biological processes of ALS. The treatment was initiated at the onset of symptoms, and we assessed the progression of the disease by neurological scores, rotarod and grip tests, as well as monitoring survival. Additionally, we examined the effects of the treatment on spinal cord and muscle degeneration in the treated mice. In both models, the administration of niclosamide resulted in a slowdown of disease progression, an increase in survival rates, and an improvement in tissue pathology. This was characterized by a reduction in gliosis, motor neuron loss, muscle atrophy, and inflammatory markers. Based on these results, our findings demonstrate that niclosamide can impact multiple pathways involved in ALS. This multi-targeted approach leads to a slowdown in the progression of the disease, thereby positioning niclosamide as a promising candidate for repurposing in the treatment of ALS.

ORGANISM(S): Mus musculus

PROVIDER: GSE249071 | GEO | 2024/05/09

REPOSITORIES: GEO

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Project description:Burgeoning evidence highlights seminal roles for microglia in the pathogenesis of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). The receptor for advanced glycation end products (RAGE) binds ligands relevant to ALS that accumulate in the diseased spinal cord and RAGE has been previously implicated in the progression of ALS pathology. We generated a novel mouse model to temporally delete Ager from microglia in the murine SOD1G93A model of ALS. Microglia Ager deficient SOD1G93A mice and controls were examined for changes in survival, motor function, gliosis, motor neuron numbers, and transcriptomic analyses of lumbar spinal cord. Furthermore, we examined bulk-RNA-sequencing transcriptomic analyses of human ALS cervical spinal cord. Transcriptomic analysis of human cervical spinal cord reveals a range of AGER expression in ALS patients, which was negatively correlated with age at disease onset and death or tracheostomy. The degree of AGER expression related to differential expression of pathways involved in extracellular matrix, lipid metabolism, and intercellular communication. Microglia display increased RAGE immunoreactivity in the spinal cords of high AGER expressing patients and in the SOD1G93A murine model of ALS vs. respective controls. We demonstrate that microglia Ager deletion at the age of symptomatic onset, day 90, in SOD1G93A mice extends survival in male but not female mice. Critically, many of the pathways identified in human ALS patients that accompanied increased AGER expression were significantly ameliorated by microglia Ager deletion in male SOD1G93A mice. Our results indicate that microglia RAGE disrupts communications with cell types including astrocytes and neurons, intercellular communication pathways that divert microglia from a homeostatic to an inflammatory and tissue-injurious program. In totality, microglia RAGE contributes to the progression of SOD1G93A murine pathology in male mice and may be relevant in human disease.

Project description:Background Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease associated with motor neuron degeneration, muscle atrophy and paralysis. To date, multiple panels of biomarkers have been described in ALS patients and murine models. Nevertheless, none of them has sufficient specificity and thus the molecular signature for ALS prognosis and progression remains to be fully elucidated. Circulating microRNAs (miRNAs) are highly stable molecules that are recently used as promising biomarkers for many types of human cancer and muscle disorders. Here we overcome this limitation through a longitudinal study, analyzing serum levels of circulating miRNAs in ALS patients during the progression of the pathology. Method We performed next-generation sequencing (NGS) analysis and absolute RT quantification of serum samples of 27 ALS patients and 11 healthy control; among them 13 ALS patients were studied every three months till the end of the disease. Results We demonstrated that miR-151a-3p, miR-206 and miR-199a-3p are significantly expressed at the mild, moderate and severe stages of ALS pathology, whereas the expression levels of miR-133a and miR-199a-5p remained low during the whole study and retain diagnostic significance in the moderate and severe stages (miR-133a) and in mild and terminal stages (miR-199a-5p) of the disease. Moreover, we analysed the miRNAs serum levels during the progression of the disease in each patient and we demonstrated that high levels of miR-206, miR-133a, miR-151a-5p, miR-151a-3p can predict a slower clinical decline of patient functionality suggesting that these miRNAs represent good potential prognostic markers for ALS disease. Conclusion This study is the first to perform a longitudinal absolute quantification of circulating miRNAs during ALS disease. We highlighted putative biomarkers for diagnosis, prognosis and disease stage identification of ALS patients providing cut-off threshold for most of the miRNAs analyzed. In addition, our results define a molecular signature of ALS phenotypes that could help to define appropriate enrollments of patients in clinical trials.

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Repurposing niclosamide in mouse models of amyotrophic lateral sclerosis

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