de Bie Josien, Guest Jade, Guillemin Gilles J, Grant Ross
Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia.
Australasian Research Institute, Sydney Adventist Hospital, Sydney, New South Wales, Australia.
J Neurochem. 2016 Mar;136(5):995-1003. doi: 10.1111/jnc.13496. Epub 2016 Jan 20.
Age is considered a dominant risk factor in the development of most neurodegenerative disorders. The kynurenine pathway, a major metabolic pathway of tryptophan is altered in the majority of neurodegenerative disorders. In this study, we have analysed CSF samples from 49 healthy women across a wide age range (0-90) for kynurenine pathway metabolites and the inflammatory marker neopterin. Our results show central tryptophan metabolism is increased with age in women, with an apparent shift towards the neurotoxin quinolinic acid. We also observed an increase in central levels of the inflammatory marker neopterin with age and a positive correlation between neopterin and kynurenine pathway activation. We conclude that, the changes that occur in the kynurenine pathway as a result of normal ageing are mechanistically linked to increased inflammatory signalling and have some explanatory potential with regard to age-associated degenerative diseases in the CNS. Management of health in ageing and (preventative) treatment would do well to look to the kynurenine pathway for potentially novel solutions. Both the inflammation marker neopterin and kynurenine pathway activity were increased with age in the CSF of female subjects. While levels of quinolinic acid (QUIN), picolinic acid (PIC), kynurenine and quinaldic acid (QA) were increased, 3-hydroxykynurenine (3HK) was decreased and 3-hydroxyanthranilic acid (3HAA) and kynurenic acid (KYNA) remained unchanged. Of particular interest is the increase in QUIN, a neuroexcitotoxin associated with neurodegeneration.
年龄被认为是大多数神经退行性疾病发生发展的主要风险因素。犬尿氨酸途径是色氨酸的主要代谢途径，在大多数神经退行性疾病中会发生改变。在本研究中，我们分析了49名年龄跨度较大（0 - 90岁）的健康女性脑脊液样本中的犬尿氨酸途径代谢产物和炎症标志物新蝶呤。我们的结果表明，女性体内中枢色氨酸代谢随年龄增长而增加，且明显向神经毒素喹啉酸转变。我们还观察到炎症标志物新蝶呤的中枢水平随年龄增长而升高，并且新蝶呤与犬尿氨酸途径激活之间呈正相关。我们得出结论，正常衰老导致的犬尿氨酸途径变化在机制上与炎症信号增强有关，并且对于中枢神经系统中与年龄相关的退行性疾病具有一定的解释潜力。在衰老过程中的健康管理以及（预防性）治疗不妨从犬尿氨酸途径寻找潜在的新解决方案。女性受试者脑脊液中炎症标志物新蝶呤和犬尿氨酸途径活性均随年龄增长而增加。虽然喹啉酸（QUIN）、吡啶甲酸（PIC）、犬尿氨酸和喹哪啶酸（QA）水平升高，但3 - 羟基犬尿氨酸（3HK）降低，3 - 羟基邻氨基苯甲酸（3HAA）和犬尿酸（KYNA）保持不变。特别值得关注的是与神经退行性变相关的神经兴奋毒素QUIN的增加。
