title: 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 (Aβ), a toxic peptide associated with neurodegeneration and cognitive abnormalities in AD. We found that Aβ1-42-induced toxicity and reduction in neurosphere proliferation were prevented by Nrf2 overexpression, while Nrf2 deficiency enhanced the Aβ1-42-induced reduction of neuronal differentiation. On the other hand, Aβ1-40 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 Aβ-induced NPC toxicity.
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Virve
authors.initials: V
authors.lastname: Kärkkäinen
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Pomeshchik
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Savchenko
authors.forename: Hiramani
authors.initials: H
authors.lastname: Dhungana
authors.forename: Antti
authors.initials: A
authors.lastname: Kurronen
authors.forename: Sarka
authors.initials: S
authors.lastname: Lehtonen
authors.forename: Nikolay
authors.initials: N
authors.lastname: Naumenko
authors.forename: Pasi
authors.initials: P
authors.lastname: Tavi
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Levonen
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Tarja
authors.initials: T
authors.lastname: Malm
authors.forename: Johanna
authors.initials: J
authors.lastname: Magga
authors.forename: Katja M
authors.initials: KM
authors.lastname: Kanninen
authors.forename: Jari
authors.initials: J
authors.lastname: Koistinaho
mesh_terms: D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D008297:Male; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D058953:Neural Stem Cells / Q000502:physiology*; D055495:Neurogenesis; D010446:Peptide Fragments / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; Neural stem cells; Neurodegeneration; Neurogenesis; Oxidative stress