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Focal white matter lesions drive grey matter inflammation, neuronal dysfunction and synapse loss

ABSTRACT: Focal white matter lesions occur in most neurodegenerative disorders. Despite occurring early in disease, white matter lesions are considered either independent of, or secondary to, grey matter neuroinflammation, synapse loss and altered neuronal activity. Notably their functional impact on neuronal circuits has been understudied. To address this, we generated a focal white matter lesion in an anatomically well-defined circuit, in which white matter lesions occur in many neurodegenerative disorders. Here we show that focal white matter lesions evoke transient neuronal activity changes and microgliosis, with subsequent synapse loss and increased microglia engulfment in the grey matter, which is reversed if myelin regeneration completes. Grey matter microgliosis is often considered detrimental but we show that it is an integral part of the myelin regenerative process. When we prevent these transient changes in the grey matter, myelin regeneration is blocked in the white matter. Conversely, inducing myelin regeneration failure leads to chronic neuroinflammation in the grey matter, suggesting that myelin regeneration failure drives sustained grey matter microglial activation. This recapitulates the low-grade inflammation considered to be a dominant mechanism underlying neurodegeneration. Our findings reveal a form of regenerative plasticity coupling white matter integrity to grey matter function - a novel mechanism of neuroplasticity that may underlie multiple neurodegenerative conditions - and highlights the potential of targeting myelin regeneration to prevent chronic inflammation.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE311781 | GEO | 2026/02/05

REPOSITORIES: GEO

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Project description:Increasing evidence indicates heterogeneity in functional and molecular properties of oligodendrocyte lineage cells both during development and under pathologic conditions. In multiple sclerosis, remyelination of grey matter lesions exceeds that in white matter. Here we used cells derived from grey matter versus white matter regions of surgically resected human brain tissue samples, to compare the capacities of human A2B5-positive progenitor cells and mature oligodendrocytes to ensheath synthetic nanofibers, and relate differences to the molecular profiles of these cells. For both cell types, the percentage of ensheathing cells was greater for grey matter versus white matter cells. For both grey matter and white matter samples, the percentage of cells ensheathing nanofibers was greater for A2B5-positive cells versus mature oligodendrocytes. Grey matter A2B5-positive cells were more susceptible than white matter A2B5-positive cells to injury induced by metabolic insults. Bulk RNA sequencing indicated that separation by cell type (A2B5-positive vs mature oligodendrocytes) is more significant than by region but segregation for each cell type by region is apparent. Molecular features of grey matter versus white matter derived A2B5-positive and mature oligodendrocytes were lower expression of mature oligodendrocyte genes and increased expression of early oligodendrocyte lineage genes. Genes and pathways with increased expression in grey matter derived cells with relevance for myelination included those related to responses to external environment, cell-cell communication, cell migration, and cell adhesion. Immune and cell death related genes were up-regulated in grey matter derived cells. We observed a significant number of up-regulated genes shared between the stress/injury and myelination processes, providing a basis for these features. In contrast to oligodendrocyte lineage cells, no functional or molecular heterogeneity was detected in microglia maintained in vitro, likely reflecting the plasticity of these cells ex vivo. The combined functional and molecular data indicate that grey matter human oligodendrocytes have increased intrinsic capacity to myelinate but also increased injury susceptibility, in part reflecting their being at a stage earlier in the oligodendrocyte lineage.

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Focal white matter lesions drive grey matter inflammation, neuronal dysfunction and synapse loss

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