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Increased 3-Hydroxykynurenine serum concentrations differentiate Alzheimer’s disease patients from controls

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European Archives of Psychiatry and Clinical Neuroscience Aims and scope Submit manuscript

Abstract

Increased degradation of tryptophan (TRP) through the kynurenine (KYN) pathway (KP) is known to be involved in the molecular mechanisms resulting in the neuropathogenesis of Alzheimer’s disease (AD). Activation of the KP leads to the production of neurotoxic metabolites 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) by immune cells and neuroprotective derivates kynurenic acid (KYNA) and picolinic acid (PIC) by astrocytes and neurons. We therefore investigated whether an imbalance between neurotoxic and neuroprotective kynurenine metabolites could be detected in patients with AD. We measured serum levels of TRP, KYNA, 3-HK, PIC and QUIN in 20 patients with AD and for comparison in 20 patients with major depression, and 19 subjectively cognitive impaired subjects. Serum levels of 3-HK were markedly increased in AD patients compared to the comparison groups (p < .0001). Serum levels of the other KP metabolites were not significantly different between groups. Our data indicate an increased production of the neurotoxic KP metabolite 3-HK in AD. In contrast to its downstream metabolites QUIN and PIC, 3-HK can cross the blood–brain barrier via an active transport process. Our data therefore indicate an enhanced availability of 3-HK in the brain of AD patients, which may be related to the previously reported higher production of QUIN in AD brains.

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Acknowledgments

We would like to thank Johanna Zach for her excellent work in performing the HPLC analyses. We also thank Lilya Jertila-Aqil and Felician Iancu for assistance. Part of this work was supported by grants from the Friedrich Baur Foundation, the BMBF (grant no. 01ES0704 to M.J.S and H.H.) and the Interdisciplinary Faculty, Department “Ageing Science and Humanities”, University of Rostock, and from the Hirnliga Foundation, Wiehl, Germany, to S.J.T. G.G. would like to acknowledge the support of the Alzheimer’s Association (IIRG-08-89545), the Rebecca Cooper Foundation (Australia), the Curran Foundation and the University of New South Wales.

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Authors and Affiliations

  1. Institute for Laboratory Medicine, University of Munich, Nussbaumstr. 7, 80336, Munich, Germany

    Markus J. Schwarz

  2. Department of Pharmacology, University of New South Wales, Sydney, Australia

    Gilles J. Guillemin

  3. German Center for Neurodegenerative Diseases (DZNE), University of Rostock, Rostock, Germany

    Stefan J. Teipel

  4. Institute for Stroke and Dementia Research, Klinikum Grosshadern, University of Munich, Munich, Germany

    Katharina Buerger

  5. Department of Psychiatry, Goethe-University, Frankfurt/Main, Germany

    Harald Hampel

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  1. Markus J. Schwarz
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Correspondence to Markus J. Schwarz.

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Schwarz, M.J., Guillemin, G.J., Teipel, S.J. et al. Increased 3-Hydroxykynurenine serum concentrations differentiate Alzheimer’s disease patients from controls. Eur Arch Psychiatry Clin Neurosci 263, 345–352 (2013). https://doi.org/10.1007/s00406-012-0384-x

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