Reduced Nrf2 expression mediates the decline in neural stem cell function during a critical middle-age period.
Although it is known that the regenerative function of neural stem/progenitor cells (NSPCs) declines with age, causal mechanisms underlying this phenomenon are not understood. Here, we systematically analyze subventricular zone (SVZ) NSPCs, in various groups of rats across the aging spectrum, using in vitro and in vivo histological and behavioral techniques. These studies indicate that although NSPC function continuously declines with advancing age, there is a critical time period during middle age (13-15 months) when a striking reduction in NSPC survival and regeneration (proliferation and neuronal differentiation) occurs. The studies also indicate that this specific temporal pattern of NSPC deterioration is functionally relevant at a behavioral level and correlates with the decreasing expression of the redox-sensitive transcription factor, Nrf2, in the NSPCs. When Nrf2 expression was suppressed in 'young' NSPCs, using short interfering RNAs, the survival and regeneration of the NSPCs was significantly compromised and mirrored 'old' NSPCs. Conversely, Nrf2 overexpression in 'old' NSPCs rendered them similar to 'young' NSPCs, and they showed increased survival and regeneration. Furthermore, examination of newborn Nrf2 knockout (Nrf2 -/-) mice revealed a lower number of SVZ NSPCs in these animals, when compared to wild-type controls. In addition, the proliferative and neurogenic potential of the NSPCs was also compromised in the Nrf2-/- mice. These results identify a novel regulatory role for Nrf2 in NSPC function during aging and have important implications for developing NSPC-based strategies to support healthy aging and to treat age-related neurodegenerative disorders.
Department of Neurology, University of Arizona, Tucson, AZ, USA.
Mandi J
MJ
Corenblum
Department of Neurology, University of Arizona, Tucson, AZ, USA.|Neuroscience and Cognitive Science Undergraduate Program, Undergraduate Biology Research Program, University of Arizona, Tucson, AZ, USA.
Sneha
S
Ray
Department of Neurology, University of Arizona, Tucson, AZ, USA.|Neuroscience and Cognitive Science Undergraduate Program, Undergraduate Biology Research Program, University of Arizona, Tucson, AZ, USA.
Quentin W
QW
Remley
Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA.
Min
M
Long
Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA.
Bryan
B
Harder
Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA.
Donna D
DD
Zhang
Department of Neurology, University of Arizona, Tucson, AZ, USA.|Departments of Psychology & Neuroscience, University of Arizona, Tucson, AZ, USA.|Evelyn F McKnight Brain Institute, University of Arizona, Tucson, AZ, USA.
Carol A
CA
Barnes
Department of Neurology, University of Arizona, Tucson, AZ, USA.|Evelyn F McKnight Brain Institute, University of Arizona, Tucson, AZ, USA.
Lalitha
L
Madhavan
D000375:Aging / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011916:Rats, Inbred F344; D012038:Regeneration
D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C495637:Nfe2l2 protein, rat
Nrf2; aging; neural stem cells; oxidative stress; redox; subventricular zone