羰基化蛋白作为阿尔茨海默病的临床标志物及其与色氨酸降解和免疫激活的关系。

Carbonyl proteins as a clinical marker in Alzheimer's disease and its relation to tryptophan degradation and immune activation.

作者信息

Greilberger Joachim, Fuchs Dietmar, Leblhuber Friedrich, Greilberger Michaela, Wintersteiger Reinhold, Tafeit Erwin

机构信息

Institute of Physiological Chemistry, Center for Physiological Medicine, Medical University Graz, Graz, Austria.

出版信息

Clin Lab. 2010;56(9-10):441-8.

PMID:21086789

Abstract

BACKGROUND

The question arises whether oxidative stress is connected with systemic immune activation in Alzheimer's disease (AD) and mild cognitive impairment (MCI). During immune response interferon-gamma stimulates the kynurenine (Kyn) pathway, a major route of L-tryptophan (Trp) degradation.

METHODS

Plasma Kyn, Trp and the Kyn to Trp ratio (Kyn/Trp), carbonyl proteins (CP) as oxidative stress parameter and homocysteine, neopterin, folate and vitamin B12 were measured from patients with AD and MCI (n = 16: 6 females and 4 males with AD, 3 females and 3 males with MCI; 63.3 +/- 13.7 years), and an age matched healthy control group (n = 15: 11 females and 4 males; 62.8 +/- 3.6 years). We correlated the oxidative stress parameter CP with the degradation of Trp creating a new quotient CP/Trp and calculated the sensitivity, specificity, and cut-off values for CP, Trp, CP/Trp, and Kyn/Trp using discriminate analysis.

RESULTS

CP was significantly higher in AD/MCI (930 +/- 265 pmol/mg; p < 0.001) compared to controls (300 +/- 120 pmol/mg), Trp was significantly lower in AD/MCI (48.9 +/- 9.0 micromol/L; p < 0.001) than controls (65.2 +/- 10.7 micromol/L). While Kyn showed no significant difference between AD/MCI (1.72 +/- 0.56 micromol/L) and controls (1.53 +/- 0.29 micromol/L), Kyn/Trp was significantly higher in AD/MCI (35.2 +/- 8.8 micromol/mmol; p < 0.001) than in controls (23.7 +/- 4.2 micromol/mmol). CP/Trp ratio was more than 4 fold higher in the AD/MCI group (19.8 +/- 7.76 [(pmol/mg)/(micromol/L)]; p < 0.001) compared to controls (4.79 +/- 2.26 [(pmol/mg)/(micromol/L)]). Homocysteine, folate, vitamin B12, and neopterin showed no significant difference. Discriminant analysis provided CP alone as the best clinical marker with highest sensitivity and highest specificity for AD/MCI followed by the ratio of CP/Trp. ROC curve analysis provided the best result for CP/Trp.

CONCLUSIONS

These preliminary results support the hypothesis that oxidative damage to proteins is directly connected with Trp degradation and Kyn pathway in the systemic immune activation.

摘要

背景

阿尔茨海默病（AD）和轻度认知障碍（MCI）中氧化应激是否与全身免疫激活相关的问题由此产生。在免疫反应过程中，γ-干扰素刺激犬尿氨酸（Kyn）途径，这是L-色氨酸（Trp）降解的主要途径。

方法

测定AD和MCI患者（n = 16：6名女性和4名男性患AD，3名女性和3名男性患MCI；63.3±13.7岁）以及年龄匹配的健康对照组（n = 15：11名女性和4名男性；62.8±3.6岁）的血浆Kyn、Trp和Kyn与Trp的比值（Kyn/Trp）、作为氧化应激参数的羰基蛋白（CP）以及同型半胱氨酸、新蝶呤、叶酸和维生素B12。我们将氧化应激参数CP与Trp的降解相关联，创建了一个新的商值CP/Trp，并使用判别分析计算了CP、Trp、CP/Trp和Kyn/Trp的敏感性、特异性和临界值。

结果

与对照组（300±120 pmol/mg）相比，AD/MCI组的CP显著更高（930±265 pmol/mg；p < 0.001），AD/MCI组的Trp显著低于对照组（48.9±9.0 μmol/L；p < 0.001）（65.2±10.7 μmol/L）。虽然AD/MCI组（1.72±0.56 μmol/L）和对照组（1.53±0.29 μmol/L）之间的Kyn无显著差异，但AD/MCI组的Kyn/Trp显著高于对照组（35.2±8.8 μmol/mmol；p < 0.001）（23.7±4.2 μmol/mmol）。与对照组（4.79±2.26 [(pmol/mg)/(μmol/L)]）相比，AD/MCI组的CP/Trp比值高出4倍多（19.8±7.76 [(pmol/mg)/(μmol/L)]；p < 0.001）。同型半胱氨酸、叶酸、维生素B12和新蝶呤无显著差异。判别分析表明，单独的CP是AD/MCI最佳的临床标志物，具有最高的敏感性和特异性，其次是CP/Trp比值。ROC曲线分析显示CP/Trp的结果最佳。