Oxenkrug Gregory, van der Hart Marieke, Roeser Julien, Summergrad Paul
Department of Psychiatry, Tufts University School of Medicine, USA.
Charles River Laboratories, S. San Francisco, USA.
Endocrinol Diabetes Metab J. 2017 Nov;1(4). Epub 2017 Nov 19.
Insulin resistance (IR), obesity and other components of metabolic syndrome [MetS] are highly associated with Alzheimer's (AD) and Parkinson's (PD) diseases. Dysregulation of kynurenine (Kyn) pathway (KP) of tryptophan (Trp) metabolism was suggested as major contributor to pathogenesis of AD and PD and MetS. KP, the major source of NAD in humans, occurs in brain and peripheral organs. Considering that some, but not all, peripherally originated derivatives of Kyn penetrate blood brain barrier, dysregulation of central and peripheral KP might have different functional impact. Up-regulated Kyn formation from Trp was discovered in central nervous system of AD and PD while assessments of peripheral KP in these diseases yield controversial results. We were interested to compare peripheral kynurenines in AD and PD with emphasis on MetS-associated kynurenines, i.e., kynurenic (KYNA) and anthranilic (ANA) acids and 3-hydroxykynurenine (3-HK). Serum concentrations of KP metabolites were evaluated (HPLC-MS method). In PD patients Trp concentrations were lower, and Kyn: Trp ratio, Kyn, ANA and KYNA were higher than in controls. 3-HK concentrations of PD patients were below the sensitivity threshold of the method. In AD patients. ANA serum concentrations were approximately 3 fold lower, and KYNA concentrations were approximately 40% higher than in controls. Our data suggest different patterns of KP dysregulation in PD and AD: systemic chronic subclinical inflammation activating central and peripheral KP in PD, and central, rather than peripheral, activation of KP in AD triggered by Aβ. Dysregulation of peripheral KP in PD and AD patients might underline association between neurodegenerative diseases and MetS.
胰岛素抵抗（IR）、肥胖及代谢综合征（MetS）的其他组分与阿尔茨海默病（AD）和帕金森病（PD）高度相关。色氨酸（Trp）代谢的犬尿氨酸（Kyn）途径（KP）失调被认为是AD、PD及MetS发病机制的主要促成因素。KP是人体中烟酰胺腺嘌呤二核苷酸（NAD）的主要来源，存在于脑和外周器官中。鉴于Kyn的一些（而非全部）外周源性衍生物可穿透血脑屏障，中枢和外周KP失调可能具有不同的功能影响。在AD和PD的中枢神经系统中发现Trp生成Kyn上调，而这些疾病中外周KP的评估结果存在争议。我们感兴趣的是比较AD和PD患者外周犬尿氨酸，重点关注与MetS相关的犬尿氨酸，即犬尿喹啉酸（KYNA）、邻氨基苯甲酸（ANA）和3-羟基犬尿氨酸（3-HK）。评估了KP代谢产物的血清浓度（采用高效液相色谱-质谱法）。与对照组相比，PD患者的Trp浓度较低，而Kyn:Trp比值、Kyn、ANA和KYNA较高。PD患者的3-HK浓度低于该方法的检测灵敏度阈值。在AD患者中，ANA血清浓度比对照组低约3倍，而KYNA浓度比对照组高约40%。我们的数据表明，PD和AD中KP失调模式不同：系统性慢性亚临床炎症激活PD中的中枢和外周KP，而AD中由淀粉样β蛋白（Aβ）触发的是中枢而非外周KP激活。PD和AD患者外周KP失调可能是神经退行性疾病与MetS之间关联的基础。
