Age‐ and disease‐specific changes of the kynurenine pathway in Parkinson’s and Alzheimer’s disease

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.

Kynurenic Acid Levels are Increased in the CSF of Alzheimer’s Disease Patients

“…Using high-performance liquid chromatography (HPLC), recent studies found increased KYNA concentration in CSF in different cohorts of AD patients [36,37]. However, it was almost simultaneously published that KYNA levels were strongly reduced in CSF from AD patients when compared with control subjects [38]. In this work, we aimed to clarify KP metabolite concentrations measured in CSF and serum and to determine their specificity in AD.…”

Are Kynurenines Accomplices or Principal Villains in Dementia? Maintenance of Kynurenine Metabolism

“…Increased KYN, KYNA, and QUIN in serum and CSF were associated with aging [50]. Altered levels of KYN metabolites have been observed in patients with AD, PD, HD, and VCD.…”

Kynurenine pathway in Parkinson's disease—An update

“…In a study, enhanced level of KYNA was assessed in the brain of 3 months and 4 months old rats, which correspondingly showed the precursor, KYN with increased levels in cortex and hippocampus regions of these rats whereas KAT increased three-fold in cortex and striatum [ 33 ]. In contrast, the level of KYNA was reduced in the CSF of PD and Alzheimer's disease (AD) patients [ 34 ].…”

“…Recently, the ratio of QUIN/KYNA and the level of QUIN were found to be higher in the plasma of PD patients [ 99 , 100 ]. Another recent KYN pathway study in PD has found that the level of KYNA was reduced in CSF with an increased level of KYN, KYNA and QUIN in serum [ 34 ]. Therefore, biomarker studies are essential to identify the early signs of PD and further profiling are useful to develop pharmacological interventions.…”

“… Biofluid Metabolites Model No. of subjects Primary outcome Analytical methods Pathway Results Conclusion Reference CSF and serum Human 105 patients Effect of age on KYN metabolites and analysis of the influence of medication use LC-MS Tryptophan metabolism ↓KYNA in CSF (n = 33 AD patients ↑ KYN, KYNA and QUIN in serum KP has a potential as a marker of disease progression or as a therapeutic target in neurodegeneration [ 34 ] n = 33 PD patients n = 39 control subjects) Serum Knurenines Human 18 PD patients Compare peripheral kynurenines with metabolic syndrome associated kynurenines HPLC Tryptophan metabolism ↓ TRP concentration 20 AD patients ↑KYN: TRP ratio, KYN, AA and KYNA Association between neurodegenerative disorders and metabolic syndromes [ 54 ] Plasma 184 metabolites Human 82 PD patients Quantified the plasma levels of metabolites LC-TOFMS Pathomechanistic pathways ↓KYNA/KYN ratio ↑ QUIN/KYNA ratio Plasma biomarkers are available for predicting PD [ 99 ] Human Catabolism of tryptophan and tyrosine in relation to the isoprenoid pathway in some neurological and psychiatric disorder HPLC ↑ QUIN Hypercatabolism of tryptophan could be a co...…”