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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.    Supplementary Information  The online version contains supplementary material available at 10.1186/s12974-021-02191-2.

journal of neuroinflammation

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