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| Status |
Public on Jun 16, 2021 |
| Title |
Microglia RAGE exacerbates the progression of neurodegeneration within the SOD1G93A murine model of amyotrophic lateral sclerosis in a sex-dependent manner |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
RNA profiles from lumbar spinal cord tissue of microglia Ager knockout mice, and Cre controls from an amyotrophic lateral sclerosis mouse model were compared.
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| Contributor(s) |
MacLean M, Juranek J, Cuddapah S, López-Díez R, Ruiz HH, Hu J, Frye L, Li H, Gugger PF, Schmidt A |
| Citation(s) |
34130712 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| F31 NS120424 |
RAGE: A Potential Contributor to Neuroinflammation in Amyotrophic Lateral Sclerosis |
NEW YORK UNIVERSITY SCHOOL OF MEDICINE |
Michael MacLean |
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| Submission date |
Oct 29, 2020 |
| Last update date |
Jun 21, 2021 |
| Contact name |
Paul Francis Gugger |
| E-mail(s) |
[email protected]
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| Organization name |
NYU Langone Health
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| Department |
Medicine
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| Street address |
435 E 30th St
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| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10016 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA673172 |
| SRA |
SRP289779 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE160402_counts.normalized.txt.gz |
1.1 Mb |
(ftp)(http) |
TXT |
| GSE160402_counts.raw.txt.gz |
532.3 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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