Proteasome activation by insulin-like growth factor-1/nuclear factor erythroid 2-related factor 2 signaling promotes exercise-induced neurogenesis
Proteasome activation by insulin-like growth factor-1/nuclear factor erythroid 2-related factor 2 signaling promotes exercise-induced neurogenesis
复制标题
胰岛素样生长因子 1/核因子红细胞 2 相关因子 2 信号传导激活蛋白酶体可促进运动诱导的神经发生。
DOI：
10.1002/stem.3102
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发表时间：
2019-11-13
期刊：
影响因子：
5.2
通讯作者：
Lu, Li
中科院分区：
文献类型：
--
作者：
Niu, Xiaojie;Zhao, Yunhe;Lu, Li
体育锻炼可以增强人类的学习和记忆能力，缓解与年龄相关的认知能力下降。然而，运动和认知改善之间的机械关系在很大程度上仍然未知。在这项研究中，我们发现运动引起的认知益处伴随着适应性海马蛋白酶体激活。自愿轮运行增加海马蛋白酶体活性在成年和中年小鼠，有助于加速神经发生，可以逆转海马内注射的蛋白酶体抑制剂MG 132。我们进一步发现，血清和海马中胰岛素样生长因子-1（IGF-1）水平的增加可能是运动诱导的蛋白酶体激活所必需的。我们的体外研究表明，IGF-1刺激蛋白酶体活性在培养的成人神经祖细胞（NPC）通过促进核因子红细胞2相关因子2（Nrf 2）的核转位，其次是蛋白酶体亚基，如PSMB 5的表达升高。相反，用选择性IGF-1 R抑制剂苦鬼臼脂素预处理成年小鼠减少了运动诱导的神经发生，同时减少了Nrf 2核转位和蛋白酶体活性。同样，通过RNA干扰双侧海马内注射重组腺相关病毒颗粒降低Nrf 2表达，显著抑制了运动诱导的蛋白酶体激活，并减弱了认知功能。总的来说，我们的工作表明，蛋白酶体激活在海马通过IGF-1/Nrf 2信号是一个关键的适应性机制，运动相关的神经发生，这可能是一个潜在的靶向途径在神经退行性变。干细胞2019
Physical exercise-induced enhancement of learning and memory, and alleviation of age-related cognitive decline in humans have been widely acknowledged. However, the mechanistic relationship between exercise and cognitive improvement remains largely unknown. In this study, we found that exercise-elicited cognitive benefits were accompanied by adaptive hippocampal proteasome activation. Voluntary wheel running increased hippocampal proteasome activity in adult and middle-aged mice, contributing to an acceleration of neurogenesis that could be reversed by intra-hippocampal injection of the proteasome inhibitor MG132. We further found that increased levels of insulin-like growth factor-1 (IGF-1) in both serum and hippocampus may be essential for exercise-induced proteasome activation. Our in vitro study demonstrated that IGF-1 stimulated proteasome activity in cultured adult neural progenitor cells (NPCs) by promoting nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), followed by elevated expressions of proteasome subunits such as PSMB5. In contrast, pretreating adult mice with the selective IGF-1R inhibitor picropodophyllin diminished exercise-induced neurogenesis, concurrent with reduced Nrf2 nuclear translocation and proteasome activity. Likewise, lowering Nrf2 expression by RNA interference with bilateral intra-hippocampal injections of recombinant adeno-associated viral particles significantly suppressed exercise-induced proteasome activation and attenuated cognitive function. Collectively, our work demonstrates that proteasome activation in hippocampus through IGF-1/Nrf2 signaling is a key adaptive mechanism underlying exercise-related neurogenesis, which may serve as a potential targetable pathway in neurodegeneration. Stem Cells 2019