Amyotrophic Lateral Sclerosis
In Vivo Imaging and Novel Therapeutic Approaches in ALS
April 29, 2022
Ann Marie Schmidt, M.D., New York University Langone Health, Grossman School of Medicine
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder. Neuroinflammation is increasingly recognized as one of the critical mechanisms underpinning this devastating incurable disease. In human and animal model ALS spinal cord, there is high expression of the receptor for advanced glycation endproducts (RAGE) and its proinflammatory ligands, especially in microglia. Microglia are specialized immune cells that are found in the central nervous system. The interaction of RAGE and its ligands, in these microglia, increases expression of pro-inflammatory molecules, reduces expression of anti-inflammatory molecules, and produces neurotoxic reactive oxygen species. Dr. Ann Marie Schmidt, a fiscal year 2016 recipient of an Amyotrophic Lateral Sclerosis Research Program Therapeutic Idea Award, found that blocking the RAGE pathway prolonged the life span and delayed neurological deterioration in ALS mouse models. Dr. Schmidt hopes that the novel small molecule RAGE antagonist drug-like compounds developed in her laboratory have the potential to function similarly in humans as in mouse models.
Dr. Schmidt’s group observed an interesting phenomenon in spinal cords of ALS mice, notably in microglia. They noted that activated microglia – those that are responding to and removing neuronal damage, a process that is mediated and triggered by the body’s own inflammatory response – have a much higher expression of RAGE when compared to the non-active or unstimulated microglia also present in the spinal cord. This finding implicates RAGE, as well as its upstream and downstream mediators, in neuronal loss, which is widely recognized as a critical mechanism driving paralysis in, and the eventual death of, ALS patients.
Dr. Schmidt’s team is delving deeper into the ways these novel small molecules suppress the RAGE pathway. Specifically, they are investigating how the RAGE pathway signal transduction tips the balance in microglia, from their default healthy repair state to a neuroinflammatory and neurotoxic state. Dr. Schmidt believes that RAGE signaling is key to the upregulation of inflammatory and pro-oxidative stress pathways, which ultimately may lead to suppression of reparative and regenerative processes and thus neuronal loss in the ALS spinal cord.
The Schmidt lab uses non-invasive imaging of the ALS mouse spinal cord to discern activated microglia (in the ALS mice) from unactivated microglia in normal mice. Data has revealed that deletion of microglial RAGE is protective in male ALS mice when compared to control mice. This suggests that RAGE in microglia exerts negative effects on motor function and survival, further strengthening the relevance of this target for ALS. Taken together, these findings hold great promise to both identify a non-invasive way to track glial inflammation and to identify a novel therapeutic target for ALS patients. These studies illustrate cell type-specific alterations in ALS and emphasize that these changes drive neurodegenerative progression and lead to aberrant intercellular communication.
When asked about her aim for the future for this work, Dr. Schmidt writes, “[we are] committed to ALS and neurodegeneration in our program and hope to continue to forge forward with progress toward clinical trials through the development of optimized small molecules, which are ready for clinical trials. We approach our work in ALS as a dedicated, multi-disciplinary research team and although it may be a Herculean task, I am very hopeful that we will get to the clinical studies.”
Much of this work was recently published in Communications Biology (https://pubmed.ncbi.nlm.nih.gov/35228715/).
Earlier stages of this award were previously published in Journal Neuroinflammation (https://pubmed.ncbi.nlm.nih.gov/34130712/).
Public and Technical Abstracts: Receptor for AGE (RAGE) Signal Transduction in Amyotrophic Lateral Sclerosis: In Vivo Imaging and Novel Therapeutic Approaches
Last updated Thursday, April 28, 2022