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Blood levels of D-amino acid oxidase vs. D-amino acids in reflecting cognitive aging.

ABSTRACT: Feasible peripheral biomarker for Alzheimer's disease (AD) is lacking. Dysregulation of N-methyl-D-aspartate (NMDA) receptor is implicated in the pathogenesis of AD. D-amino acid oxidase (DAO) and amino acids can regulate the NMDA receptor function. This study aimed to examine whether peripheral DAO and amino acids levels are characteristic of age-related cognitive decline. We enrolled 397 individuals (including amnestic mild cognitive impairment (MCI), mild AD, moderate to severe AD, and healthy elderly). DAO levels in the serum were measured using ELISA. Amino acids levels in serum were measured by high performance liquid chromatography. Severity of the cognitive deficits in subjects was assessed using Clinical Dementia Rating Scale (CDR). The DAO levels increased with the severity of the cognitive deficits. DAO levels were significantly associated with D-glutamate and D-serine levels. The Receiver Operating Characteristics analysis of DAO levels for AD patients vs. healthy controls determined the optimal cutoff value, 30.10, with high sensitivity (0.842) and specificity (0.889) (area under curve = 0.928). This is the first study indicating that the peripheral DAO levels may increase with age-related cognitive decline. The finding supports the hypofunction of NMDA receptor hypothesis in AD. Whether DAO could serve as a potential surrogate biomarker needs further studies.

SUBMITTER: Lin CH

PROVIDER: S-EPMC5665939 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Hippocampal metabolism of amino acids by L-amino acid oxidase is involved in fear learning and memory.

Project description:Amino acids participate directly and indirectly in many important biochemical functions in the brain. We focused on one amino acid metabolic enzyme, L-amino acid oxidase (LAO), and investigated the importance of LAO in brain function using LAO1 knockout (KO) mice. Compared to wild-type mice, LAO1 KO mice exhibited impaired fear learning and memory function in a passive avoidance test. This impairment in LAO1 KO mice coincided with significantly reduced hippocampal acetylcholine levels compared to wild-type mice, while treatment with donepezil, a reversible acetylcholine esterase inhibitor, inhibited this reduction. Metabolomic analysis revealed that knocking out LAO1 affected amino acid metabolism (mainly of phenylalanine [Phe]) in the hippocampus. Specifically, Phe levels were elevated in LAO1 KO mice, while phenylpyruvic acid (metabolite of Phe produced largely by LAO) levels were reduced. Moreover, knocking out LAO1 decreased hippocampal mRNA levels of pyruvate kinase, the enzymatic activity of which is known to be inhibited by Phe. Based on our findings, we propose that LAO1 KO mice exhibited impaired fear learning and memory owing to low hippocampal acetylcholine levels. Furthermore, we speculate that hippocampal Phe metabolism is an important physiological mechanism related to glycolysis and may underlie cognitive impairments, including those observed in Alzheimer's disease.

| S-EPMC6056520 | biostudies-literature

Structural basis for potent inhibition of d-amino acid oxidase by thiophene carboxylic acids.

Project description:A series of thiophene-2-carboxylic acids and thiophene-3-carboxylic acids were identified as a new class of DAO inhibitors. Structure-activity relationship (SAR) studies revealed that small substituents are well-tolerated on the thiophene ring of both the 2-carboxylic acid and 3-carboxylic acid scaffolds. Crystal structures of human DAO in complex with potent thiophene carboxylic acids revealed that Tyr224 was tightly stacked with the thiophene ring of the inhibitors, resulting in the disappearance of the secondary pocket observed with other DAO inhibitors. Molecular dynamics simulations of the complex revealed that Tyr224 preferred the stacked conformation irrespective of whether Tyr224 was stacked or not in the initial state of the simulations. MM/GBSA indicated a substantial hydrophobic interaction between Tyr244 and the thiophene-based inhibitor. In addition, the active site was tightly closed with an extensive network of hydrogen bonds including those from Tyr224 in the stacked conformation. The introduction of a large branched side chain to the thiophene ring markedly decreased potency. These results are in marked contrast to other DAO inhibitors that can gain potency with a branched side chain extending to the secondary pocket due to Tyr224 repositioning. These insights should be of particular importance in future efforts to optimize DAO inhibitors with novel scaffolds.

| S-EPMC6193832 | biostudies-literature

Interplay between microbial d-amino acids and host d-amino acid oxidase modifies murine mucosal defence and gut microbiota.

Project description:L-Amino acids are the building blocks for proteins synthesized in ribosomes in all kingdoms of life, but d-amino acids (d-aa) have important non-ribosome-based functions(1). Mammals synthesize d-Ser and d-Asp, primarily in the central nervous system, where d-Ser is critical for neurotransmission(2). Bacteria synthesize a largely distinct set of d-aa, which become integral components of the cell wall and are also released as free d-aa(3,4). However, the impact of free microbial d-aa on host physiology at the host-microbial interface has not been explored. Here, we show that the mouse intestine is rich in free d-aa that are derived from the microbiota. Furthermore, the microbiota induces production of d-amino acid oxidase (DAO) by intestinal epithelial cells, including goblet cells, which secrete the enzyme into the lumen. Oxidative deamination of intestinal d-aa by DAO, which yields the antimicrobial product H2O2, protects the mucosal surface in the small intestine from the cholera pathogen. DAO also modifies the composition of the microbiota and is associated with microbial induction of intestinal sIgA. Collectively, these results identify d-aa and DAO as previously unrecognized mediators of microbe-host interplay and homeostasis on the epithelial surface of the small intestine.

| S-EPMC5074547 | biostudies-literature

Blood levels of d-amino acids reflect the clinical course of COVID-19.

Project description:d-Amino acids, rare enantiomers of amino acids, have been identified as biomarkers and therapeutic options for COVID-19. Methods for monitoring recovery are necessary for managing COVID-19. On the other hand, the presence of SARS-CoV2 virus in the blood is associated with worse outcomes. We investigated the potential of d-amino acids for assessing recovery from severe COVID-19. In patients with severe COVID-19 requiring artificial ventilation, the blood levels of d-amino acids, including d-alanine, d-proline, d-serine, and d-asparagine, which were lower than the normal range before treatment, quickly and transiently increased and surpassed the upper limit of the normal range. This increase preceded the recovery of respiratory function, as indicated by ventilation weaning. The increase in blood d-amino acid levels was associated with the disappearance of the virus in the blood, but not with inflammatory manifestations or blood cytokine levels. d-Amino acids are sensitive biomarkers that reflect the recovery of the clinical course and blood viral load. Dynamic changes in blood d-amino acid levels are key indicators of clinical course.

| S-EPMC9988715 | biostudies-literature

Glycyrrhizic acid improves cognitive levels of aging mice by regulating T/B cell proliferation

Project description:We implemented transcriptomic analyses of blood of 12M mice; These mice with the treatment of Glycyrrhizic acid for 6 weeks.

2020-06-18 | GSE146239 | GEO

Amino Acids Whose Intracellular Levels Change Most During Aging Alter Chronological Life Span of Fission Yeast.

Project description:Amino acid deprivation or supplementation can affect cellular and organismal life span, but we know little about the role of concentration changes in free, intracellular amino acids during aging. Here, we determine free amino acid levels during chronological aging of nondividing fission yeast cells. We compare wild-type with long-lived mutant cells that lack the Pka1 protein of the protein kinase A signalling pathway. In wild-type cells, total amino acid levels decrease during aging, but much less so in pka1 mutants. Two amino acids strongly change as a function of age: glutamine decreases, especially in wild-type cells, while aspartate increases, especially in pka1 mutants. Supplementation of glutamine is sufficient to extend the chronological life span of wild-type but not of pka1Δ cells. Supplementation of aspartate, on the other hand, shortens the life span of pka1Δ but not of wild-type cells. Our results raise the possibility that certain amino acids are biomarkers of aging, and their concentrations during aging can promote or limit cellular life span.

| S-EPMC7812441 | biostudies-literature

Expression of D-Amino Acid Oxidase (DAO/DAAO) and D-Amino Acid Oxidase Activator (DAOA/G72) during Development and Aging in the Human Post-mortem Brain.

Project description:In the brain, D-amino acid oxidase (DAO/DAAO) mainly oxidizes D-serine, a co-agonist of the N-methyl-D-aspartate (NMDA) receptors. Thus, DAO can regulate the function of NMDA receptors via D-serine breakdown. Furthermore, DAO activator (DAOA)/G72 has been reported as both DAOA and repressor. The co-expression of DAO and DAOA genes and proteins in the human brain is not yet elucidated. The aim of this study was to understand the regional and age span distribution of DAO and DAOA (mRNA and protein) in a concomitant manner. We determined DAO and DAOA mRNA and protein expression across six brain regions in normal human post-mortem brain samples (16 weeks of gestation to 91 years) using quantitative real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. We found higher expression of DAO mRNA in the cerebellum, whereas lower expression of DAO protein in the cerebellum compared to the other brain regions studied, which suggests post-transcriptional regulation. We detected DAOA protein but not DAOA mRNA in all brain regions studied, suggesting a tightly regulated expression. To understand this regulation at the transcriptional level, we analyzed DNA methylation levels at DAO and DAOA CpG sites in the cerebellum and frontal cortex of control human post-mortem brain obtained from Gene Expression Omnibus datasets. Indeed, DAO and DAOA CpG sites in the cerebellum were significantly more methylated than those in the frontal cortex. While investigating lifespan effects, we found that DAO mRNA levels were positively correlated with age <2 years in the cerebellum and amygdala. We also detected a significant positive correlation (controlled for age) between DAO and DAOA protein in all of the brain regions studied except for the frontal cortex. In summary, DAO and DAOA expression in the human brain are both age and brain region dependent.

| S-EPMC5382383 | biostudies-literature

Extent reflecting overall dietary amino acids composition adherence to the human requirement amino acids pattern is associated with the development of type 2 diabetes.

Project description:This study aimed to elucidate whether dietary amino acids (AAs) composition is associated with type 2 diabetes mellitus (T2DM) and to investigate how serum AAs profiles mediated this association. Two prospective cohorts of 1750 and 4024 adults were enrolled. Dietary AAs compositions index (AACI) was developed to reflect the overall quality of dietary AAs composition. Multivariate linear regression and logistic regression models were used to examine associations of AACI and T2DM. The AACI was associated with the incidence of T2DM with the relative risk and 95%CI from the bottom to the top tertiles being 1.00, 1.49 (0.88-2.51) and 2.27 (1.20-4.28), and 1.00, 1.58 (1.13-2.19) and 2.33 (1.56-3.47) in the two cohorts, respectively. The AACI was positively associated with serum valine, isoleucine, glutamic acid and phenylalanine, and it was negatively associated with serum glycine and histidine in both cohorts (P<0.01). Valine, glutamic acid and histidine consistently and partially mediated the association between the AACI and T2DM in the two cohorts, with total mediation effects of 33.4% and 54.6%, respectively. Dietary AAs composition was associated with the incidence of T2DM, meanwhile, the relationship was mediated by some degree of serum AAs. Future dietary strategies should focus on the improvement of the overall quality of dietary AAs compositions.

| S-EPMC8064212 | biostudies-literature

Involvement of D-amino acid oxidase in elimination of free D-amino acids in mice.

Project description:The physiological role of D-amino acid oxidase was investigated by using mutant ddY/DAO- mice lacking the enzyme. Free D-amino acid concentrations in the mutant mice were significantly higher than those of control ddY/DAO+ mice in kidney, liver, lung, heart, brain, erythrocytes, serum and urine. The results suggest that the enzyme is involved in the catabolism of free D-amino acids in the body, and that free D-amino acids are also excreted into urine.

| S-EPMC1135571 | biostudies-other

Glycyrrhizic Acid Improves Cognitive Levels of Aging Mice by Regulating T/B Cell Proliferation.

Project description:Glycyrrhizic acid (GA) is the substance with the highest content of triterpenoid saponins that can be extracted from licorice, and has anti-inflammatory, neuroprotective, and anticancer functions, among others. The aim of this study was to investigate the protective effect of GA on cognitive decline in middle-aged mice and explore its mechanisms. We injected GA by the tail vein of C57BL/6 mice and measured their cognitive levels using the Morris water maze. The Morris water maze results demonstrated that GA improved learning and memory abilities in middle-aged mice. Furthermore, the RNA-sequencing and flow cytometric analyses revealed that GA could increase T and B cells. We then confirmed the relationship between cognition and the immune system in the immune-deficient B-NDG mouse model. Our results suggest that GA improves cognition in aging mice by regulating T/B cell proliferation.

| S-EPMC7575738 | biostudies-literature

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