Using a combination of gene expression profiling and comparative bioinformatics, we examined whether regionally distinct gene profiling could inform how oligodendrocytes contribute to neuropsychiatric disease.

Oligodendrocytes exist in diverse populations that vary in density throughout the central nervous system with a proposed heterogeneity of function including non-myelinating roles. Oligodendrocytes are implicated in multiple neuropsychiatric diseases including dementia. Cortical oligodendrocytes are uniquely positioned to play a key role in neurodegeneration by synchronizing circuit connectivity but specific molecular pathways are presently lacking.

We utilized oligodendrocyte-specific translating ribosome affinity purification and RNA-seq (TRAP-seq) coupled with weighted gene co-expression network analysis (WGCNA) to transcriptionally profile adult mature oligodendrocytes from different regions of the central nervous system in mice to identify and characterize distinct region-specific gene networks.

We identified two gene networks that uniquely define cortical oligodendrocytes and differentially regulate either cortical myelination or synaptic signaling. These two cortical oligodendrocyte gene networks are enriched for genes associated with dementia, including MAPT, and multiple gene targets of the regulatory microRNA, miR-142-3p. Using a combination of TRAP-qPCR, miR-142-3p overexpression in vitro, and miR-142-null mice, we show that miR-142-3p modulates these networks and negatively regulates cortical myelination. In rTg4510 tau-overexpressing mice, a well-studied model of dementia pathogenesis, cortical myelination is compromised, and tau-mediated neurodegeneration is associated with gene co-expression networks that recapitulate both cortical oligodendrocyte gene networks and alter cellular pathways in both the cortex and the hippocampus, a key brain region affected in Alzheimer disease. We further demonstrate these overlapping gene networks from normal cortical mature oligodendrocytes are present and disease-associated in existing datasets from human tauopathies.

Our approach identified two gene networks specific to cortical oligodendrocytes with distinct biologic functions associated with tau-mediated neurodegeneration in both mouse and human. We provide evidence connecting the plastic control of cortical myelination, via miR-142-3p regulation, to human neurodegenerative disease.