Disease-associated oligodendrocyte responses across neurodegenerative diseases

Oligodendrocyte dysfunction has been implicated in the pathogenesis of neurodegenerative diseases, so un-derstanding oligodendrocyte activation states would shed light on disease processes. We identify three distinct activation states of oligodendrocytes from single-cell RNA sequencing (RNA-seq) of mouse models of Alzheimer's disease (AD) and multiple sclerosis (MS): DA1 (disease-associated1, associated with immuno-genic genes), DA2 (disease-associated2, associated with genes influencing survival), and IFN (associated with interferon response genes). Spatial analysis of disease-associated oligodendrocytes (DAOs) in the cu-prizone model reveals that DA1 and DA2 are established outside of the lesion area during demyelination and that DA1 repopulates the lesion during remyelination. Independent meta-analysis of human single-nucleus RNA-seq datasets reveals that the transcriptional responses of MS oligodendrocytes share features with mouse models. In contrast, the oligodendrocyte activation signature observed in human AD is largely distinct from those observed in mice. This catalog of oligodendrocyte activation states (http://research-pub.gene. com/OligoLandscape/) will be important to understand disease progression and develop therapeutic inter-ventions.

Automated summary

This study identifies three distinct activation states of oligodendrocytes and reveals the differences in their expression characteristics in different diseases through single-cell RNA sequencing analysis of mouse and human models. The catalog of oligodendrocyte activation states is important for understanding disease progression and developing therapeutic interventions.