Disease-associated Oligodendrocyte Responses Across Neurodegenerative Diseases

Oligodendrocyte dysfunction has been implicated in the pathogenesis of neurodegenerative diseases, so understanding their activation states would shed new light on disease processes. We identify three distinct activation states of oligodendrocytes from single-cell RNA-seq of mouse models of Alzheimer’s Disease (AD) and Multiple Sclerosis (MS): DA1 (disease-associated1, associated with immunogenic genes), DA2 (disease-associated2, associated with genes influencing survival) and IFN (associated with interferon response genes). Spatial analysis of DAOs in the cuprizone model show that DA1 and DA2 establish outside of the lesion area during demyelination and DA1 repopulate the lesion during remyelination. Independent meta-analysis of human single-nuclei RNA-seq datasets reveal that the transcriptional responses of MS oligodendrocytes share features with mouse models. In contrast, the oligodendrocyte activation signatures observed in human AD is largely distinct from those observed in mice. This catalog (http://research-pub.gene.com/OligoLandscape/) of oligodendrocyte activation states will be important for understanding disease progression and developing novel therapeutic interventions.