| First Author | MacLean M | Year | 2021 |
| Journal | J Neuroinflammation | Volume | 18 |
| Issue | 1 | Pages | 139 |
| PubMed ID | 34130712 | Mgi Jnum | J:357593 |
| Mgi Id | MGI:6814300 | Doi | 10.1186/s12974-021-02191-2 |
| Citation | MacLean M, et al. (2021) Microglia RAGE exacerbates the progression of neurodegeneration within the SOD1(G93A) murine model of amyotrophic lateral sclerosis in a sex-dependent manner. J Neuroinflammation 18(1):139 |
| abstractText | 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. |
