Department of Neurology and Alzheimer Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
J Neurochem. 2019 Dec;151(5):656-668. doi: 10.1111/jnc.14843. Epub 2019 Aug 25.
The kynurenine (Kyn) pathway, which regulates neuroinflammation and N-methyl-d-aspartate receptor activation, is implicated in Parkinson's disease (PD) and Alzheimer's disease (AD). Age-related changes in Kyn metabolism and altered cerebral Kyn uptake along large neutral amino acid transporters, could contribute to these diseases. To gain further insight into the role and prognostic potential of the Kyn pathway in PD and AD, we investigated systemic and cerebral Kyn metabolite production and estimations of their transporter-mediated uptake in the brain. Kyn metabolites and large neutral amino acids were retrospectively measured in serum and cerebrospinal fluid (CSF) of clinically well-characterized PD patients (n = 33), AD patients (n = 33), and age-matched controls (n = 39) using solid-phase extraction-liquid chromatographic-tandem mass spectrometry. Aging was disease independently associated with increased Kyn, kynurenic acid and quinolinic acid in serum and CSF. Concentrations of kynurenic acid were reduced in CSF of PD and AD patients (p = 0.001; p = 0.002) but estimations of Kyn brain uptake did not differ between diseased and controls. Furthermore, serum Kyn and quinolinic acid levels strongly correlated with their respective content in CSF and Kyn in serum negatively correlated with AD disease severity (p = 0.002). Kyn metabolites accumulated with aging in serum and CSF similarly in PD patients, AD patients, and control subjects. In contrast, kynurenic acid was strongly reduced in CSF of PD and AD patients. Differential transporter-mediated Kyn uptake is unlikely to majorly contribute to these cerebral Kyn pathway disturbances. We hypothesize that the combination of age- and disease-specific changes in cerebral Kyn pathway activity could contribute to reduced neurogenesis and increased excitotoxicity in neurodegenerative disease.
犬尿酸（Kyn）途径调节神经炎症和 N-甲基-D-天冬氨酸受体激活，与帕金森病（PD）和阿尔茨海默病（AD）有关。Kyn 代谢的年龄相关变化和通过大中性氨基酸转运蛋白改变的大脑 Kyn 摄取，可能导致这些疾病。为了更深入地了解 Kyn 途径在 PD 和 AD 中的作用和预后潜力，我们研究了系统性和大脑 Kyn 代谢产物的产生，并估计了它们在大脑中的转运体介导的摄取。使用固相萃取-液相色谱-串联质谱法，回顾性地测量了临床上特征明确的 PD 患者（n=33）、AD 患者（n=33）和年龄匹配对照者（n=39）的血清和脑脊液（CSF）中的 Kyn 代谢产物和大中性氨基酸。衰老与血清和 CSF 中 Kyn、犬尿氨酸和喹啉酸的增加独立相关。PD 和 AD 患者的 CSF 中犬尿氨酸酸浓度降低（p=0.001；p=0.002），但患病和对照组之间的 Kyn 脑摄取估计值没有差异。此外，血清 Kyn 和喹啉酸水平与其 CSF 中的相应含量强烈相关，血清 Kyn 与 AD 疾病严重程度呈负相关（p=0.002）。Kyn 代谢产物在 PD 患者、AD 患者和对照组的血清和 CSF 中随年龄增长而积累。相比之下，犬尿氨酸酸在 PD 和 AD 患者的 CSF 中强烈减少。差异转运体介导的 Kyn 摄取不太可能对这些大脑 Kyn 途径紊乱有主要贡献。我们假设大脑 Kyn 途径活性的年龄和疾病特异性变化的组合可能导致神经发生减少和神经退行性疾病中的兴奋性毒性增加。
