Nrf2 Regulates Neurogenesis and Protects Neural Progenitor Cells Against Aβ Toxicity

Abstract

Neural stem/progenitor cells (NPCs) proliferate and produce new neurons in neurogenic areas throughout the lifetime. While these cells represent potential therapeutic treatment of neurodegenerative diseases, regulation of neurogenesis is not completely understood. We show that deficiency of nuclear factor erythroid 2-related factor (Nrf2), a transcription factor induced in response to oxidative stress, prevents the ischemia-induced increase in newborn neurons in the subgranular zone of the dentate gyrus. Consistent with this finding, the growth of NPC neurospheres was increased by lentivirus-mediated overexpression of Nrf2 gene or by treatment with pyrrolidine dithiocarbamate (PDTC), an Nrf2 activating compound. Also, neuronal differentiation of NPCs was increased by Nrf2 overexpression or PDTC treatment but reduced by Nrf2 deficiency. To investigate the impact of Nrf2 on NPCs in Alzheimer's disease (AD), we treated NPCs with amyloid beta (Ab), a toxic peptide associated with neurodegeneration and cognitive abnormalities in AD. We found that Ab 1-42 -induced toxicity and reduction in neurosphere proliferation were prevented by Nrf2 overexpression, while Nrf2 deficiency enhanced the Ab 1-42 -induced reduction of neuronal differentiation. On the other hand, Ab 1-40 had no effect on neurosphere proliferation in wt NPCs but increased the proliferation of Nrf2 overexpressing neurospheres and reduced it in Nrf2-deficient neurospheres. These results suggest that Nrf2 is essential for neuronal differentiation of NPCs, regulates injury-induced neurogenesis and provides protection against Ab-induced NPC toxicity.

A Whole Methylome CpG-SNP Association Study of Psychosis in Blood and Brain Tissue

“…68 Furthermore, Nrf2 is essential for neuronal differentiation of neural stem/progenitor cells, regulates injuryinduced neurogenesis, and provides protection against amyloid-beta-induced toxicity. 69 Being in the potential promoter of ENC1, the methylation of rs16872141 could potentially suppress transcription of this gene. However, rs16872141 was not significant in GWAS studies of the Swedish samples used in the present study (P-value = .303; 5001 cases and 6243 controls), 28 nor the recent PGC2 metaanalysis (P-value = .739; 36 989 cases and 113 075 controls).…”

Applications of the Keap1–Nrf2 system for gene and cell therapy

“…Furthermore, Nrf2-deficiency prevents ischemia-induced neurogenesis, suggesting the involvement of this transcription factor in regenerative processes after acute brain pathology [116] . Very recently Nrf2 gene transfer was shown to be protective in acute nerve damage [117] .…”

“…While several studies have investigated the role of the Keap1-Nrf2 system in stem cells knockdown studies that under physiological conditions Nrf2 functions in the promotion of proliferation and neuronal differentiation of NSCs without influencing their migration [204] .…”

“…Recently we demonstrated that Nrf2 regulates neurogenesis in a mouse model of global brain ischemia [204] . Ischemia-induced proliferation of NSCs was severely impaired in Nrf2-deficient mice, indicating that Nrf2 is required for endogenous neurogenesis following a brain insult.…”

Redox-regulated fate of neural stem progenitor cells

“…In this regard, it was shown that NRF2 is essential for ischemia-induced neurogenesis in the SGZ niche [123]. In vitro, ectopic expression of NRF2 or treatment with a NRF2 activating compound, pyrrolidine dithiocarbamate, increases NSPCs self-renewal under proliferating conditions and supports neuronal differentiation upon mitogen withdrawal [123].…”