Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Department of Human Anatomy, School of Basic Medicine, Binzhou Medical University, Yantai 264003, China.
Theranostics. 2020 Aug 1;10(21):9674-9685. doi: 10.7150/thno.43829. eCollection 2020.
Adult hippocampal neurogenesis (AHN) deficits contribute to the progression of cognitive impairments during accelerated senescence, with the mechanistic causes poorly understood. Glycogen synthase kinase-3β (GSK-3β) is a critical regulator in prenatal neurodevelopment. The present study aims to study whether and how GSK-3β regulates AHN during the accelerated senescence. AHN and AHN-dependent cognition and GSK-3β were evaluated in 3- and 6-month senescence-accelerated mice prone 8 (SAM-P8) and senescence resistant 1 (SAM-R1) mice, respectively. GSK-3β was selectively overexpressed in wild-type mice using adeno-associated virus, or knocked-out by crossbreeding with GSK-3β 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. AHN transiently increased at 3-month, but dramatically dropped at 6-month of age in SAM-P8 mice with a simultaneous activation of GSK-3β at 3-month. Selective overexpression of GSK-3β 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-3β by SB216763 efficiently preserved AHN and improved contextual memory in 6-month SAM-P8 mice, while conditional knock-out of GSK-3β in NSCs impaired AHN. Early-stage activation of GSK-3β in NSCs impairs AHN by accelerating the depletion of NSC pool, and pharmacological inhibition of GSK-3β 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.
成人海马神经发生 (AHN) 缺陷导致加速衰老过程中认知障碍的进展，其机制原因尚不清楚。糖原合成酶激酶-3β (GSK-3β) 是产前神经发育的关键调节因子。本研究旨在研究 GSK-3β 是否以及如何在加速衰老过程中调节 AHN。分别在 3 个月和 6 个月的快速衰老加速型 8 号小鼠（SAM-P8）和衰老抵抗 1 号小鼠（SAM-R1）中评估 AHN 和 AHN 依赖性认知以及 GSK-3β。使用腺相关病毒在野生型小鼠中选择性过表达 GSK-3β，或通过与 Nestin-Cre 小鼠中的 GSK-3β 基因敲除小鼠杂交在神经干细胞（NSCs）中敲除 GSK-3β，或在 SAM-P8 小鼠中用 SB216763 药理学抑制 GSK-3β。通过 BrdU、DCX 染色和逆转录病毒标记评估 AHN。在 SAM-P8 小鼠中，AHN 在 3 个月时短暂增加，但在 6 个月时急剧下降，同时在 3 个月时 GSK-3β 被激活。在野生型小鼠的海马 NSCs 中选择性过表达 GSK-3β会导致 NSC 池的快速耗竭，从而导致长期的 AHN 缺陷，尽管它会短暂增加新生神经元的增殖和存活。用 SB216763 药理学抑制 GSK-3β可有效保留 6 个月 SAM-P8 小鼠的 AHN，并改善情景记忆，而 NSCs 中的 GSK-3β 条件性敲除则会损害 AHN。早期在 NSCs 中激活 GSK-3β会通过加速 NSC 池的耗竭来损害 AHN，而 GSK-3β 的药理学抑制在加速衰老过程中有效保留 AHN。这些结果揭示了加速衰老过程中 AHN 损伤的新机制，并为相关疾病的促神经发生治疗提供了新的靶点。
