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Cited by 33Amyotrophic Lateral Sclerosis ResearchNeuroinflammation and Neurodegeneration MechanismsAdvanced Glycation End Products research

Microglia RAGE exacerbates the progression of neurodegeneration within the SOD1G93A murine model of amyotrophic lateral sclerosis in a sex-dependent manner

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MacLean, Michael, Juranek, Judyta, Cuddapah, Swetha, López-Díez, Raquel, Ruiz, Henry H., Hu, Jiyuan, Frye, Laura, Li, Huilin +2 more·2021·Journal of Neuroinflammation
DOI 10.1186/s12974-021-02191-2PMC PMC8207569
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Abstract

Background: 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. Methods: We generated a novel mouse model to temporally delete Ager from microglia in the murine SOD1 G93A model of ALS. Microglia Ager deficient SOD1 G93A 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. Results: 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 SOD1 G93A murine model of ALS vs. respective controls. We demonstrate that microglia Ager deletion at the age of symptomatic onset, day 90, in SOD1 G93A 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 SOD1 G93A mice. Conclusions: 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 SOD1 G93A murine pathology in male mice and may be relevant in human disease.

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  • Transcriptomic analysis of cervical spinal cord from ALS patients revealed that RAGE expression was negatively correlated with disease severity and age of disease onset.

    “A transcriptomic analysis of cervical spinal cord from ALS patients revealed that RAGE expression was negatively correlated with disease severity and the age of disease onset.”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [342]

    The Results section, “Evaluation of AGER expression in human amyotrophic lateral sclerosis spinal cord” (page unavailable), reports a negative correlation between cervical spinal cord AGER expression and age at disease onset, although the reported p value is 0.07. It also reports a negative correlation with age at death or tracheostomy, not with a measure of disease severity. The disease-severity portion of the claim is therefore unsupported by the reported analysis. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Microglia-specific knockout of RAGE at disease onset extended survival of only male, and not female, hSOD1 G93A transgenic mice.

    “However, the microglia-specific knockout of RAGE at disease onset extended the survival of only male, and not female, hSOD1 G93A transgenic mice.342”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [342]

    The Results section reports longer survival in male SOD1G93A mice after microglial Ager deletion, with no lifespan difference in females. It says tamoxifen was administered at 90 days of age to induce deletion, but does not establish that this was disease onset, which the paper defines separately as the age of maximum weight. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • RAGE expression level was closely linked to signaling pathways related to extracellular matrix composition, cell-cell communication and lipid metabolism.

    “The RAGE expression level was closely linked to signaling pathways related to extracellular matrix composition, cell-cell communication and lipid metabolism.342”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [342]

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Authors
MacLean, M., Juranek, J., Cuddapah, S., López-Díez, R., Ruiz, H. H., Hu, J., Frye, L., Li, H., Gugger, P. F., & Schmidt, A. M.
Affiliations
  • New York University (US)
  • University of Warmia and Mazury in Olsztyn (PL)
  • NYU Langone Health (US)
Corresponding author
Schmidt, Ann Marie
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2021-06-15
Volume
18
Issue
1
Pages
139-139
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/s12974-021-02191-2
PMC
PMC8207569
OpenAlex
W3169139204
Cited by
33
References
95
Citations by year
2026: 5 · 2025: 6 · 2024: 6 · 2023: 8 · 2022: 7 · 2021: 1
FWCI
2.63
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Defense (W81XWH-17-1-0346)
  • National Institute of Neurological Disorders and Stroke (F31NS120424)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
Keywords
amyotrophic lateral sclerosis, microglia, receptor for advanced glycation end products, RAGE, SOD1 G93A mice, sex differences, microglial reprogramming, intercellular communication, spinal cord transcriptome, extracellular matrix, lipid metabolism, neuroinflammation, disease progression
MeSH terms
Receptor for Advanced Glycation End Products, Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis, Animals, Astrocytes, Disease Models, Animal, Female, Gliosis, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Motor Neurons, Sex Characteristics, Spinal Cord, Sequence Analysis, RNA, Microglia, Disease Progression, Mice

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