Age-dependent changes in the glutamate-nitric oxide pathway in the hippocampus of the triple transgenic model of Alzheimer's disease: implications for neurometabolic regulation
Age-dependent changes in the glutamate-nitric oxide pathway in the hippocampus of the triple transgenic model of Alzheimer's disease: implications for neurometabolic regulation
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DOI：
10.1016/j.neurobiolaging.2016.06.012
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发表时间：
2016-10-01
影响因子：
4.2
通讯作者：
Ledo, Ana
中科院分区：
文献类型：
--
作者：
Dias, Candida;Lourenco, Catia F.;Ledo, Ana
一氧化氮(NO)- n中心点)浓度动态的年龄依赖性变化可能在阿尔茨海默病（AD）突触和代谢功能衰退中发挥重要作用。这种神经调节剂在突触前起作用，增加囊泡释放和谷氨酸能传递，并调节线粒体功能。在细胞内氧化还原环境改变的条件下，(NO)- n中心点可能发生反应，产生过氧亚硝酸盐等活性物质。采用三倍转基因AD小鼠模型（3xTgAD），研究了海马谷氨酸-(NO)- n中心点轴的年龄依赖性变化。直接测量(NO)- n -中心点浓度动态变化显示，3xTgAD模型早期n -甲基- d -天冬氨酸型受体诱发峰(NO)- n -中心点显著增加。老化使转基因模型的峰值(NO)- n -中心点降低，产量和衰减率显著降低。能量代谢评估显示，两种基因型小鼠的基础耗氧量随年龄增加而降低，线粒体氧化磷酸化参数普遍降低，线粒体保留能力下降。最后，我们观察到海马中3-硝基酪氨酸残基的年龄依赖性增加，这与(NO)- n中心点生物活性向与神经毒性相关的氧化化学的转移的假设一致。(C) 2016 Elsevier Inc.版权所有。
Age-dependent changes in nitric oxide ((NO)-N-center dot) concentration dynamics may play a significant role in both decaying synaptic and metabolic functions in Alzheimer's disease (AD). This neuromodulator acts presynaptically to increase vesicle release and glutamatergic transmission and also regulates mitochondrial function. Under conditions of altered intracellular redox environment, (NO)-N-center dot may react and produce reactive species such as peroxynitrite. Using the triple transgenic mouse model of AD (3xTgAD), we investigated age-dependent changes in the glutamate-(NO)-N-center dot axis in the hippocampus. Direct measurement of (NO)-N-center dot concentration dynamics revealed a significant increase in N-methyl-D-aspartate type receptor-evoked peak (NO)-N-center dot in the 3xTgAD model at an early age. Aging produced a decrease in peak (NO)-N-center dot accompanied by significant decrease in production and decay rates in the transgenic model. Evaluation of energy metabolism revealed age-dependent decrease in basal oxygen consumption rate, a general decrease in mitochondrial oxidative phosphorylation parameters, and loss in mitochondrial sparing capacity in both genotypes. Finally, we observed age-dependent increase in 3-nitrotyrosine residues in the hippocampus, consistent with a putative shift in (NO)-N-center dot bioactivity toward oxidative chemistry associated with neurotoxicity. (C) 2016 Elsevier Inc. All rights reserved.