School of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
School of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
Free Radic Biol Med. 2019 Mar;133:169-178. doi: 10.1016/j.freeradbiomed.2018.09.002. Epub 2018 Sep 4.
Astrocyte-neuron interactions protect neurons from iron-mediated toxicity. As dopamine can be metabolized to reactive quinones, dopaminergic neurons are susceptible to oxidative damage and ferroptosis-like induced cell death. Detoxification enzymes are required to protect neurons. Brain-derived neurotrophic factor (BDNF) plays a key role in the regulation of redox sensitive transcription factor Nrf2 in astrocytes and metabolic cooperation between astrocytes and neurons. This article reviews the importance of BDNF and astrocyte-neuron interactions in the protection of neurons against oxidative damages in rodent brains. We previously proposed that BDNF activates Nrf2 via the truncated TrkB.T1 and p75 receptor complex in astrocytes. Stimulation by BDNF generates the signaling molecule ceramide, which activates PKCζ leading to induction of the CK2-Nrf2 signaling axis. As a cell clock regulates p75 expression, we suggested that BDNF effectively activates Nrf2 in astrocytes during the rest phase. In contrast, neurons express both TrkB.FL and TrkB.T1, and TrkB.FL tyrosine kinase activity inhibits p75-dependent ceramide generation and internalizes p75. Therefore, BDNF may not effectively activate Nrf2 in neurons. Notably, neurons only weakly activate detoxification and antioxidant enzymes/proteins via the Nrf2-ARE signaling axis. Thus, astrocytes may provide relevant transcripts and/or proteins to neurons via microparticles/exosomes increasing neuronal resistance to oxidative stress. Circadian increases in the levels of circulating glucocorticoids may further facilitate material transfer from astrocytes to neurons via the stimulation of pannexin 1 channels-P2X7R signaling pathway in astrocytes at the beginning of the active phase. Dysregulation of astrocyte-neuron interactions could therefore contribute to the pathogenesis of neurodegenerative diseases including Parkinson's disease.
星形胶质细胞-神经元相互作用可保护神经元免受铁介导的毒性。由于多巴胺可代谢为反应性醌，多巴胺能神经元易受氧化损伤和铁死亡样诱导的细胞死亡。需要解毒酶来保护神经元。脑源性神经营养因子（BDNF）在调节星形胶质细胞中氧化还原敏感转录因子 Nrf2 和星形胶质细胞与神经元之间的代谢协作方面发挥着关键作用。本文综述了 BDNF 和星形胶质细胞-神经元相互作用在保护啮齿动物大脑神经元免受氧化损伤中的重要性。我们之前提出，BDNF 通过星形胶质细胞中的截断型 TrkB.T1 和 p75 受体复合物激活 Nrf2。BDNF 的刺激产生信号分子神经酰胺，激活 PKCζ 导致 CK2-Nrf2 信号轴的诱导。由于细胞时钟调节 p75 的表达，我们认为 BDNF 在休息期有效地激活星形胶质细胞中的 Nrf2。相比之下，神经元表达 TrkB.FL 和 TrkB.T1，并且 TrkB.FL 酪氨酸激酶活性抑制 p75 依赖性神经酰胺的产生并内化 p75。因此，BDNF 可能不会有效地激活神经元中的 Nrf2。值得注意的是，神经元仅通过 Nrf2-ARE 信号轴弱激活解毒和抗氧化酶/蛋白。因此，星形胶质细胞可能通过微颗粒/外泌体向神经元提供相关的转录物和/或蛋白，从而增加神经元对氧化应激的抵抗力。循环糖皮质激素水平的昼夜节律增加可能通过刺激星形胶质细胞中的连接蛋白 1 通道-P2X7R 信号通路，在活动期开始时进一步促进物质从星形胶质细胞向神经元的转移。星形胶质细胞-神经元相互作用的失调可能导致包括帕金森病在内的神经退行性疾病的发病机制。
