Glutamine acts as a neuroprotectant against DNA damage, beta-amyloid and H2O2-induced stress.
Glutamine acts as a neuroprotectant against DNA damage, beta-amyloid and H2O2-induced stress.
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DOI：
10.1371/journal.pone.0033177
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Herrup K
中科院分区：
文献类型：
--
作者：
Chen J;Herrup K
谷氨酰胺是人体血液中最丰富的游离氨基酸，对细胞是“有条件必需的”。它的细胞内水平受通过特定运输系统摄取细胞外谷氨酰胺和通过谷氨酰胺合成酶（GS）在细胞内合成的调节。增加了调控的复杂性，当细胞外谷氨酰胺减少时，GS蛋白水平上升。不幸的是，这种过量的GS可能是不适应的。GS过表达具有神经毒性，特别是当细胞处于低谷氨酰胺培养基中时。同样，在低谷氨酰胺的情况下，多种应激反应蛋白的水平降低，使细胞对H2O2、锌盐和DNA损伤过敏。这些改变的反应可能与衰老的神经退行性疾病特别相关。在阿尔茨海默病（AD）患者的大脑中，GS活性和谷氨酰胺水平较低，与对照组相比，部分AD海马神经元的GS水平显著升高。我们证实了这些观察结果的重要性，表明提高培养基中的谷氨酰胺水平可以保护培养的神经元细胞免受淀粉样肽Aβ的侵害。此外，在两种不同的家族性AD小鼠模型中，补充10天的谷氨酰胺可以降低炎症诱导的神经元细胞周期激活、tau磷酸化和atm激活，同时提高两种突触蛋白VAMP2和synaptophysin的水平。总之，我们的观察结果表明，健康的神经元细胞需要细胞内和细胞外的谷氨酰胺，补充谷氨酰胺的神经保护作用可能有益于治疗阿尔茨海默病。
Glutamine is the most abundant free amino acid in the human blood stream and is ‘conditionally essential’ to cells. Its intracellular levels are regulated both by the uptake of extracellular glutamine via specific transport systems and by its intracellular synthesis by glutamine synthetase (GS). Adding to the regulatory complexity, when extracellular glutamine is reduced GS protein levels rise. Unfortunately, this excess GS can be maladaptive. GS overexpression is neurotoxic especially if the cells are in a low-glutamine medium. Similarly, in low glutamine, the levels of multiple stress response proteins are reduced rendering cells hypersensitive to H2O2, zinc salts and DNA damage. These altered responses may have particular relevance to neurodegenerative diseases of aging. GS activity and glutamine levels are lower in the Alzheimer's disease (AD) brain, and a fraction of AD hippocampal neurons have dramatically increased GS levels compared with control subjects. We validated the importance of these observations by showing that raising glutamine levels in the medium protects cultured neuronal cells against the amyloid peptide, Aβ. Further, a 10-day course of dietary glutamine supplementation reduced inflammation-induced neuronal cell cycle activation, tau phosphorylation and ATM-activation in two different mouse models of familial AD while raising the levels of two synaptic proteins, VAMP2 and synaptophysin. Together, our observations suggest that healthy neuronal cells require both intracellular and extracellular glutamine, and that the neuroprotective effects of glutamine supplementation may prove beneficial in the treatment of AD.
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