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Nrf2 deficiency increases oligodendrocyte loss, demyelination, neuroinflammation and axonal damage in an MS animal model

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Abstract

Oxidative stress is a pathophysiological hallmark of many CNS diseases, among multiple sclerosis (MS). Accordingly, boosting the astrocytic transcription factor nuclear factor E2-related factor 2 (Nrf2) system in an MS mouse model efficiently ameliorates oligodendrocyte loss, neuroinflammation and axonal damage. Moreover, Dimethylfumarate, an efficient activator of Nrf2, has recently been approved as therapeutic option in MS treatment. Here, we use the cuprizone mouse model of MS to induce oxidative stress, selective oligodendrocyte loss, microglia and astrocyte activation as well as axonal damage in both wild type and Nrf2-deficient mice. We found increased oligodendrocyte apoptosis and loss, pronounced neuroinflammation and higher levels of axonal damage in cuprizone-fed Nrf2-deficient animals when compared to wild type controls. In addition, Nrf2-deficient animals showed a higher susceptibility towards cuprizone within the commissura anterior white matter tract, a structure that is relatively insensitive to cuprizone in wild type animals. Our data highlight the cuprizone model as a suitable tool to study the complex interplay of oxidative stress, neuroinflammation and axonal damage. Further studies will have to show whether distinct expression patterns of Nrf2 are involved in the variable susceptibility towards cuprizone in the mouse.

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Correspondence to Tim Clarner.

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Supplementary figure 1

Comparison of cellular parameters is shown between wild type animals and Nrf2−/− animals in sagittal sliced brains stained against myelin protein PLP, microglia marker Iba1 and astrocyte protein GFAP. Myelination in Nrf2−/− animals was comparable to WT animals and no differences can be observed in between the genotypes regarding cellular density, morphology or numbers of positively stained cells. (PNG 2723 kb)

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Nellessen, A., Nyamoya, S., Zendedel, A. et al. Nrf2 deficiency increases oligodendrocyte loss, demyelination, neuroinflammation and axonal damage in an MS animal model. Metab Brain Dis 35, 353–362 (2020). https://doi.org/10.1007/s11011-019-00488-z

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