GSK-3? activation accelerates early-stage consumption of Hippocampal Neurogenesis in senescent mice.
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ABSTRACT: Adult hippocampal neurogenesis (AHN) deficits contribute to the progression of cognitive impairments during accelerated senescence, with the mechanistic causes poorly understood. Glycogen synthase kinase-3? (GSK-3?) is a critical regulator in prenatal neurodevelopment. The present study aims to study whether and how GSK-3? regulates AHN during the accelerated senescence. Methods: AHN and AHN-dependent cognition and GSK-3? were evaluated in 3- and 6-month senescence-accelerated mice prone 8 (SAM-P8) and senescence resistant 1 (SAM-R1) mice, respectively. GSK-3? was selectively overexpressed in wild-type mice using adeno-associated virus, or knocked-out by crossbreeding with GSK-3? floxed mice in the neural stem cells (NSCs) of Nestin-Cre mice, or pharmacologically inhibited with SB216763 in SAM-P8 mice. AHN was evaluated by BrdU-, DCX-staining and retrovirus-labeling. Results: AHN transiently increased at 3-month, but dramatically dropped at 6-month of age in SAM-P8 mice with a simultaneous activation of GSK-3? at 3-month. Selective overexpression of GSK-3? in hippocampal NSCs of wildtype mice induced long-term AHN deficits due to an accelerated depletion of NSC pool, although it transiently increased the proliferation and survival of the newborn neurons. Pharmacologically inhibiting GSK-3? by SB216763 efficiently preserved AHN and improved contextual memory in 6-month SAM-P8 mice, while conditional knock-out of GSK-3? in NSCs impaired AHN. Conclusion: Early-stage activation of GSK-3? in NSCs impairs AHN by accelerating the depletion of NSC pool, and pharmacological inhibition of GSK-3? is efficient to preserve AHN during the accelerated aging. These results reveal novel mechanisms underlying the AHN impairments during accelerated senescence and provide new targets for pro-neurogenic therapies for related diseases.
SUBMITTER: Liu F
PROVIDER: S-EPMC7449917 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
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