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Metabolic phenotyping reveals a reduction in the bioavailability of serotonin and kynurenine pathway metabolites in both the urine and serum of individuals living with Alzheimer’s disease

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Background: Both serotonergic signalling disruption and systemic inflammation have been associated with the pathogenesis of Alzheimer’s disease (AD). The common denominator linking the two is the catabolism of the essential amino acid, tryptophan. Metabolism via tryptophan hydroxylase results in serotonin synthesis, whilst metabolism via indoleamine 2,3-dioxygenase (IDO) results in kynurenine and its downstream derivatives. IDO is reported to be activated in times of host systemic inflammation and therefore is thought to influence both pathways. To investigate metabolic alterations in AD, a large-scale metabolic phenotyping study was conducted on both urine and serum samples collected from a multi-centre clinical cohort, consisting of individuals clinically diagnosed with AD, mild cognitive impairment (MCI) and age-matched controls. Methods: Metabolic phenotyping was applied to both urine (n = 560) and serum (n = 354) from the European-wide AddNeuroMed/Dementia Case Register (DCR) biobank repositories. Metabolite data were subsequently interrogated for inter-group differences; influence of gender and age; comparisons between two subgroups of MCI - versus those who remained cognitively stable at follow-up visits (sMCI); and those who underwent further cognitive decline (cMCI); and the impact of selective serotonin reuptake inhibitor (SSRI) medication on metabolite concentrations. Results: Results revealed significantly lower metabolite concentrations of tryptophan pathway metabolites in the AD group: serotonin (urine, serum), 5-hydroxyindoleacetic acid (urine), kynurenine (serum), kynurenic acid (urine), tryptophan (urine, serum), xanthurenic acid (urine, serum), and kynurenine/tryptophan ratio (urine). For each listed metabolite, a decreasing trend in concentrations was observed in-line with clinical diagnosis: control > MCI > AD. There were no significant differences in the two MCI subgroups whilst SSRI medication status influenced observations in serum, but not urine. Conclusions: Urine and serum serotonin concentrations were found to be significantly lower in AD compared with controls, suggesting the bioavailability of the neurotransmitter may be altered in the disease. A significant increase in the kynurenine/tryptophan ratio suggests that this may be a result of a shift to the kynurenine metabolic route due to increased IDO activity, potentially as a result of systemic inflammation. Modulation of the pathways could help improve serotonin bioavailability and signalling in AD patients.

Original languageEnglish
Article number20
JournalAlzheimer's Research and Therapy
Issue number1
Pages (from-to)20
Publication statusPublished - 9 Jan 2021

Bibliographical note

Funding Information:
The UK Dementia Research Institute (DRI) is an initiative funded by the Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. AddNeuroMed (ANM) was supported by InnoMed (Innovative Medicines in Europe), an integrated project funded by the European Union of the sixth framework priority (FP6-2004-LIFESCIHEALTH). We acknowledge support for the Dementia Case Register (DCR) and for all sample management from the NIHR Biomedical Research Centre hosted at Kings College London and the South London and Maudsley NHS Foundation Trust and funded by the National Institute for Health Research under its Biomedical Research Centres initiative. The National Phenome Centre (NPC) is supported by the Medical Research Council and National Institute for Health Research [grant number MC_PC_12025]. Infrastructure support was provided by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health or other funders.

Publisher Copyright:
© 2021, The Author(s).

    Research areas

  • Alzheimer Disease, Biological Availability, Humans, Kynurenine/metabolism, Serotonin, Tryptophan/metabolism

ID: 69207372