Age- and disease-specific changes of the kynurenine pathway in Parkinson's and Alzheimer's disease

Freek J H Sorgdrager, Yannick Vermeiren, Martijn Van Faassen, Claude van der Ley, Ellen A A Nollen, Ido P Kema, Peter P De Deyn, Freek J H Sorgdrager, Yannick Vermeiren, Martijn Van Faassen, Claude van der Ley, Ellen A A Nollen, Ido P Kema, Peter P De Deyn

Abstract

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.

Keywords: Alzheimer’s disease; Parkinson’s disease; ageing; kynurenic acid; kynurenine; neurodegeneration.

© 2019 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.

Figures

Figure 1
Figure 1
Aging affects peripheral and central Kyn pathway metabolites but not LNAAs. (a) Trp is taken up from the diet and processed intra‐ and extrahepatically. Kyn metabolites are mainly produced in extrahepatic tissue. (b) Trp, Kyn, and 3‐HK compete with LNAA for transport across the BBB. (c) In the brain, the Kyn pathway is segregated based on cell‐type; astrocytes mainly produce KA while microglia produce quinolinic acid. These metabolites can be released in the extracellular space and CSF. (d) Scatterplot showing the relationship between age and standardized scores for Trp and Kyn metabolites or LNAAs (e) in serum and CSF of controls, PD and AD patients. The best‐fit line from linear regression (including 95% confidence interval) as well as the F‐value is provided for model comparison. *p < 0.01 for F‐tests. 3‐Hk, 3‐hydroxykynurenine; AD, Alzheimer’s disease; BBB, blood–brain barrier; CSF, cerebrospinal fluid; Ile, isoleucine; KA, kynurenic acid; Kyn, kynurenine; Leu, leucine; LNAA, large neutral amino acids; PD, Parkinson’s disease; Phe, phenylalanine; Trp, tryptophan; Tyr, tyrosine; Val, valine; XA, xanthurenic acid. *p < 0.01.
Figure 2
Figure 2
Specific alterations in central Kyn pathway activity in PD and AD but no evidence of altered transporter‐mediated Kyn brain transport. (a) Scatter plots showing serum and CSF concentrations for Trp and Kyn metabolites, LNAA (b) and indices for transporter‐mediated brain uptake of Trp, Kyn and 3‐HK (c) in control (green), PD (orange), and AD (purple) patients (for serum: n = 38, 31 and 32–33, respectively; for CSF: n = 34–35, 26, and 29–32, respectively). Median and estimated 95% confidence intervals are provided. Log scales are used in case of skewed distribution. *p < 0.01, #p < 0.05 for Mann–Whitney U tests comparing control to PD or AD. Abbreviations as in Fig. 1. LOQ, limit of quantification.
Figure 3
Figure 3
Peripheral Kyn pathway metabolites as biomarkers for brain Kyn pathway activity and in AD disease severity. (a) Scatterplot showing the relationship between serum and CSF metabolite concentrations (standardized scores) for healthy controls (n = 34), PD (n = 24), and AD (n = 32) patients. The best‐fit line from linear regression (including 95% confidence interval) as well as the F‐value is provided to compare models. *p < 0.01 for F‐tests. (b) Table that shows correlation coefficients between Kyn metabolites (in serum or CSF) and AD disease severity measured by MMSE (with a lower score indicating more severe disease). *p < 0.01, #p < 0.05 for Spearman’s rank correlation coefficient. (c) Hypothetical model of findings. Aging is associated with increased Trp metabolism toward the Kyn pathway. This increases brain Kyn content either directly or as a result of increased systemic uptake. This causes increased production of Kyn metabolites including KA and QA. In PD and AD, cerebral KA content seems to be lower. This could be associated with altered NMDA receptor activity and impact the course of these diseases. Abbreviations as in Fig. 1. MMSE, mini‐mental state examination; NMDA, N‐methyl‐d‐aspartate.

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