Dimethyl Fumarate Enhances Neural Stem Cell (NSC) Self-renewal and Neuroprotection in a Human Cellular Model of Multiple Sclerosis Inflammation-induced Neurodegeneration (P8-6.014)

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 quantified the effect of DMF in NSCs self-renewal and found an increase that correlated with NRF2 expression. We quantified the proliferation and apoptosis of neuroblasts and OPCs that was reduced in the Th1 treated samples but increased in the Th1/DMF samples. There was a significant increase in the number of apoptotic neural progenitors that is improved by DMF treatment. We showed that DMF protects neural progenitor cells that conserve the migratory phenotype and neurogenesis with DMF treated Th1 cultures, associated with more self-organized migration. 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. Disclosure: Dr. Watanabe has nothing to disclose. Mr. FEDORKO has nothing to disclose. Dr. Imitola has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis . The institution of Dr. Imitola has received research support from biogen. Dr. Imitola has a non-compensated relationship as a Board Member with National MS Society that is relevant to AAN interests or activities. Dr. Imitola has a non-compensated relationship as a Committee Member with International Society for Stem Cell Research that is relevant to AAN interests or activities.