Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA; Department of Pharmacology, Shandong University School of Medicine, Jinan, China.
Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
Neuroscience. 2014 Jan 17;257:41-8. doi: 10.1016/j.neuroscience.2013.10.060. Epub 2013 Nov 4.
The interaction between neurons, astrocytes and endothelial cells plays a central role coupling energy supply with changes in neuronal activity. For a long time it was believed that glucose was the only source of energy for neurons. However, a growing body of experimental evidence indicates that lactic acid, generated by aerobic glycolysis in perivascular astrocytes, is also a source of energy for neuronal activity, particularly when the supply of glucose from the intravascular space is interrupted. Adenosine monophosphate-activated protein kinase (AMPK) is an evolutionary conserved kinase that couples cellular activity with energy consumption via induction of the uptake of glucose and activation of the glycolytic pathway. The uptake of glucose by the blood-brain barrier is mediated by glucose transporter-1 (GLUT1), which is abundantly expressed in endothelial cells and astrocytic end-feet processes. Tissue-type plasminogen activator (tPA) is a serine proteinase that is found in endothelial cells, astrocytes and neurons. Genetic overexpression of neuronal tPA or treatment with recombinant tPA protects neurons from the deleterious effects of metabolic stress or excitotoxicity, via a mechanism independent of tPA's ability to cleave plasminogen into plasmin. The work presented here shows that exposure to metabolic stress induces the rapid release of tPA from murine neurons but not from astrocytes. This tPA induces AMPK activation, membrane recruitment of GLUT1, and GLUT1-mediated glucose uptake in astrocytes and endothelial cells. Our data indicate that this is followed by the synthesis and release of lactic acid from astrocytes, and that the uptake of this lactic acid via the monocarboxylate transporter-2 promotes survival in neurons exposed to metabolic stress.
神经元、星形胶质细胞和内皮细胞之间的相互作用在将能量供应与神经元活动的变化耦合中起着核心作用。长期以来，人们一直认为葡萄糖是神经元唯一的能量来源。然而，越来越多的实验证据表明，有氧糖酵解在血管周围星形胶质细胞中产生的乳酸也是神经元活动的能量来源，尤其是当血管内空间的葡萄糖供应中断时。单磷酸腺苷激活的蛋白激酶（AMPK）是一种进化上保守的激酶，通过诱导葡萄糖摄取和激活糖酵解途径，将细胞活性与能量消耗偶联起来。血脑屏障对葡萄糖的摄取由葡萄糖转运蛋白-1（GLUT1）介导，GLUT1 在内皮细胞和星形胶质细胞终足过程中大量表达。组织型纤溶酶原激活物（tPA）是一种丝氨酸蛋白酶，存在于内皮细胞、星形胶质细胞和神经元中。神经元 tPA 的基因过表达或用重组 tPA 处理可保护神经元免受代谢应激或兴奋毒性的有害影响，其机制与 tPA 裂解纤溶酶原成纤溶酶的能力无关。这里介绍的工作表明，代谢应激会诱导小鼠神经元迅速释放 tPA，但不会从星形胶质细胞中释放 tPA。这种 tPA 诱导 AMPK 激活、GLUT1 膜募集以及 GLUT1 介导的星形胶质细胞和内皮细胞中的葡萄糖摄取。我们的数据表明，随后星形胶质细胞合成和释放乳酸，通过单羧酸转运蛋白-2 摄取这种乳酸可促进代谢应激下神经元的存活。
