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

Abstract

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.

Nutrition, Gut Microbiota, and Alzheimer's Disease

“…The samples obtained from AD patients showed a deficit of orthologs engaged into the biosynthesis of the amino acids involved in the metabolism of neurotransmitters ( 71 ). These results are in line with other studies which revealed the dysregulation of tryptophan metabolic pathways in AD patients ( 72 , 73 ).…”

Serotonin Promotes Serum Albumin Interaction with the Monomeric Amyloid β Peptide

“…The revealed influence of SRO on the HSA–Aβ interaction could be relevant to AD progression, considering the disintegration of the serotonergic system during AD, accompanied by a decrease in the SRO level in biofluids [ 15 , 16 , 39 ]. The SRO concentration in plasma is 0.28–1.7 µM [ 40 ], but in the synaptic cleft it may reach 6 mM and 55 nM after SRO diffuses into the extracellular compartment [ 41 ].…”

“…Serotonin (SRO; 5-hydroxytryptamine, 5-HT) is a HSA ligand closely related to AD pathogenesis (reviewed in [ 15 , 16 ]). It is a phylogenetically conserved monoamine neurotransmitter that performs various physiological functions (behavior regulation, appetite suppression, regulation of energy intake, storage, and expenditure, respiratory drive, hemostasis, etc.)…”

“…Numerous studies have demonstrated degeneration of the serotonin system in AD, a decline in the cortical/serum SRO level, and negative consequences of disruption in serotonergic signaling [ 15 , 16 ]. The serotonergic deficits in AD are more prominent compared with those for other neurotransmitters.…”

Roles and Mechanisms of Gut Microbiota in Patients With Alzheimer’s Disease

“…Wu et al (2021) also found that gut microbiota metabolites such as tryptophan metabolites, SCFAs and lithocholic acid are different between AD and controls, which are correlated with altered microbiota and cognitive impairment. In addition, urine and serum serotonin concentrations were found to be significantly lower in patients with AD than in controls (Whiley et al, 2021). Metabolic dysfunction is a basic characteristic of AD.…”