To determine if  the NRF2 expressed in interneurons, OPCs, NSCs is neuroprotective. 

MS Inflammation targets neural and oligodendrocyte progenitors’ (OPCs) intrinsic transcriptional programs, regenerative capacity and neuronal vulnerability. One significant hurdle is the lack of models to recapitulate the impact of inflammation of human cells. Furthermore, human models to directly test new or repurposed medications to test neuroprotection and repair are needed, since MS progression may involve failure of multiple cellular systems. Dimethyl fumarate (DMF) is used for relapsing remitting MS. Notably, it has been shown that DMF by acting on the transcription factor NRF2 (NFE2L2) can exert therapeutic mechanisms in vivo.

To study the effects of DMF in neuroinflammation, we used Th1 cytokines (IFN-g and TNF-a), that we have shown alter cerebral organoids using single RNAseq.  We exposed organoids to IFN-g100 u/ml, TNF-a 10 ng/ml alone and  treatment with DMF 300 mM. We used confocal microscopy and immunohistochemistry to quantify apoptosis, proliferation and differentiation.

We conclude that DMF enhances self-renewal and neuroprotection in a human cellular model of neuroinflammation. These experiments demonstrate applicability of  a DMF/NRF2 pathway in human models with the neurodegeneration seen in MS, this research supports that neuroprotection of neurons may be useful to target CNS compartmentalized inflammation.