Role Of Glycogen Synthase Kinase-3β Upregulation In Senescence-associated Deficits Of Adult Hippocampal Neurogenesis And The Underlying Mechanisms

Background Adult hippocampal neurogenesis(AHN)deficits contribute to the cognitive decline during aging,Alzheimer’s disease,and other processes,with the mechanistic cause poorly understood.Glycogen synthase kinase-3β(GSK-3β)plays an important role in the development of the nervous system and neurodegenerative diseases.This study aimed to investigate whether and how GSK-3β regulates AHN during accelerated aging.Methods AHN was assessed by Brd U,DCX immunostaining and retroviral labeling in 3 and 6 month-old senescene-accelerated mice prone8(SAM-P8)and senescence resistant 1 mice(SAM-R1).AHN-related cognitive functions,expression and activity of GSK-3β were also detected in these mice.GSK-3β was selectively overexpressed using adenoassociated virus,or knocked-out by crossbreeding with GSK-3β floxed mice in the neural stem cells(NSCs)of Nestin-Cre mice to study the effect of GSK-3β on AHN and related cognitive functions in adult mice.Finally,the salvage effect of GSK-3β selective inhibitor SB216763 on AHN and related cognitive dysfunction in SAM-P8 mice was tested.Results 1.Compared with SAM-R1 mice of the same age,the number of AHNs of 3-month-old SAM-P8 mice was increased,but the dendritic length and complexity of neonatal neurons were reduced.However,the number of AHNs of 6-month-old SAM-P8 mice was decreased,Neuron dendrite length,complexity,and dendritic spine density were significantly reduced,accompanied by changes in synapse-related protein expression,AHN-related pattern separation,and spatial learning-memory changes.2.Compared with SAM-R1 mice of the same age,the expression of GSK-3β in the dentate gyrus region of 3-month-old SAM-P8 mice increased,and the activity of GSK-3β was significantly enhanced.The expression and the activity of GSK-3β in the dentate gyrus region of 3-month-old SAM-P8 mice is same with SAM-R1 mice.3.Selective overexpression of human-derived GSK-3β in hippocampal NSCs of wildtype mice promotes the survival of neonatal neurons.The number of AHNs increases in the short term(4 weeks),together with the dendritic complexity of neonatal neurons increases,and dendritic ridge Density decreased.However,the number of AHNs decreased in the long term(8 weeks),the dendritic complexity of neonatal neurons,and the density of dendritic decreased significantly,due to the accelerated consumption of the NSC pool.4.GSK-3β-specific inhibitor SB216763 can effectively promote AHN in 6-month-old SAM-P8 mice and improve pattern separation dysfunction.5.The number of AHNs decreased and the complexity of neonatal neuron dendrites decreased after GSK-3β completely knocked out.Selective semi-knock-out of GSK-3β in wild-type mouse NSC had no significant effect on AHN.Conclusion The expression and activation of GSK-3β in NSC plays an important role in maintaining mouse AHN.In senescence-accelerated mice,the increase of GSK-3β expression and the enhancement of its activity can accelerate the depletion of the NSC pool,resulting in AHN increasing in the short term but decreasing in the long term accompanied by deteriorate dendritic differentiation.Inhibiting GSK-3β over-activation can effectively protect AHN damage in rapidly aging mice and improve related cognitive functions.These results reveal that the over-activation of intracellular GSK-3β in hippocampal NSCs during accelerated aging is an important mechanism that causes AHN damage and provides new molecular targets for the neuronal therapy of related diseases.