Is the Urea Cycle Involved in Alzheimer's Disease?

Hansmannel, Franck; Sillaire, Adeline Rollin; Kamboh, M. Ilyas; Lendon, Corinne; Pasquier, Florence; Hannequin, Didier; Laumet, Geoffroy; Mounier, Anaïs; Ayral, Anne Marie; DeKosky, Steven T.; Hauw, J. J.; Berr, Claudine; Mann, David; Amouyel, Philippe; Campion, Dominique; Lambert, Jean‐Charles

doi:10.3233/jad-2010-100630

Cited by 71 publications

(63 citation statements)

References 36 publications

(39 reference statements)

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“…The accumulation of ammonia in Alzheimer's disease (hyperammonemia) and consequent dyshomeostasis of urea-related metabolites has been associated with reduced glutamine synthetase activity (Seiler, 2002) and enzymatic deficiencies in the urea cycle (Hansmannel et al, 2010). However, the extra decrease found in the IL-4 knockout mice compared with the APP/PS1 mice (although not statistically significant, Fig.…”

Section: Discussionmentioning

confidence: 94%

Metabolomic research on the role of interleukin-4 in Alzheimer’s disease

et al. 2015

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Abstract:Inflammation plays a prominent role in the pathogenesis of Alzheimer's disease, affecting both brain and the peripheral system. Thus, modulation of inflammation in animal models of this neurodegenerative disorder may be of great interest to elucidate the pathological mechanisms underlying this inflammatory component. To this end, a metabolomic investigation on a triple transgenic mouse model obtained by crossing the APP/PS1 mice with interleukin-4 knockout mice (a model of impaired immune function) was performed for the first time. Serum samples from transgenic mice and wild type animals were analyzed by direct infusion mass spectrometry followed by multivariate statistics in order to identify altered metabolites. Subsequently, metabolic pathway analysis allowed the elucidation of potential pathological mechanisms associated with the development of Alzheimer-type disorders in response to interleukin-4 deficiency, such as impaired homeostasis of histamine, altered metabolism of amino acids (threonine, aspartate and tyrosine), deregulated urea cycle and increased production of eicosanoids. Therefore, this work demonstrates the potential of this triple transgenic model with modulated immunity for the study of pathological mechanisms associated with inflammation in Alzheimer's disease. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation COMMENTS FOR THE AUTHOR:Reviewer #1: The authors have not included some important requests for clarification to be added to the manuscript by the reviewer therefor another minor revision is required. Abstract still poorly writtenFor example this sentence:Thereby, the investigation of this inflammatory component presents a great potential for the elucidation of pathological mechanisms underlying to disease, the discovery of potential markers of diagnosis and the development of novel therapeutic approaches Abstract was rewritten. Authors commentWe did not use internal standards because we considered that the validation of reproducibility in metabolomic methods is better assessed using QC samples. In this sense, Naz et al. recently described that "although spiking some selected metabolites could give a good approach to the general behaviour of the method, results cannot be assumed for all the components in the sample" (J Chromatogr A 2014;1353:99). Instead, biological QCs show a similar composition to real samples, so they are preferable for validating non-targeted approaches. Thus, "the se of QCs in non-targeted metabolomics analysis can be considered as equivalent to the use of standards in routine target analysis". Reviewer comment: I don't agree with this statement how can you account for a one off issue and internal standards are also in the sample matrix. You need add this justification to the manuscriptInternal standards must present similar physico-chemical properties to the chemical species of interest in the sample. However, metabolomics approaches are not focused on individual compounds, so the use of internal standards in these method...

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Section: Discussionmentioning

confidence: 94%

Metabolomic research on the role of interleukin-4 in Alzheimer’s disease

et al. 2015

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“…Decreased urea content (Table 1) supports a disturbed homeostasis of ammonia via the urea cycle, which may elicit deleterious effects on the central nervous system and has been closely related to AD pathology [39]. Thereby, an abnormal content of urea and related amino acids has been previously found in serum [19,20,33] and brain [8,9] of AD, accompanied by altered levels of expression in different enzymes and the corresponding genes [40]. Other studies reported an increased concentration of inosine in response to an accelerated degradation of nucleotides in brain from human patients [41] and APP/PS1 mice [9], which is finally reflected in peripheral blood as revealed our metabolomic fingerprinting platform.…”

Section: Biological Hypothesismentioning

confidence: 88%

Application of metabolomics based on direct mass spectrometry analysis for the elucidation of altered metabolic pathways in serum from the APP/PS1 transgenic model of Alzheimer's disease

González‐Domínguez

García-Barrera

Vitórica

et al. 2015

Journal of Pharmaceutical and Biomedical Analysis

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Metabolomic analysis of brain tissue from transgenic mouse models of Alzheimer's disease has demonstrated a great potential for the study of pathological mechanisms and the development of new therapies and biomarkers for diagnosis. However, in order to translate these investigations to the clinical practice it is necessary to corroborate these findings in peripheral samples. To this end, this work considers the application of a novel metabolomic platform based on the combination of a two-steps extraction procedure with complementary analysis by direct infusion electrospray mass spectrometry and flow infusion atmospheric pressure photoionization mass spectrometry for a holistic investigation of metabolic abnormalities in serum samples from APP/PS1 mice. A number of metabolites were found to be perturbed in this mouse model, including increased levels of di- and tri-acylglycerols, eicosanoids, inosine, choline and glycerophosphoethanolamine; reduced content of cholesteryl esters, free fatty acids, lysophosphocholines, amino acids, energy-related metabolites, phosphoethanolamine and urea, as well as abnormal distribution of phosphocholines depending on the fatty acid linked to the molecular moiety. This allowed the elucidation of possible pathways disturbed underlying to disease (abnormal homeostasis of phospholipids leading to membrane breakdown, energy-related failures, hyperammonemia and hyperlipidemia, among others), thus demonstrating the utility of peripheral samples to investigate pathology in the APP/PS1 model.

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“…The significant reduction in urea levels (Table 4) pointed to a perturbation of the urea cycle, responsible for controlling ammonia concentrations in the organism. In Alzheimer's disease, the alteration of this pathway has been previously demonstrated on the basis of altered levels of expression in different enzymes and the corresponding genes [65]. To conclude changes observed in homocarnosine and glutathione, important antioxidants involved in the defense of the central nervous system, could be related to oxidative damage in brain.…”

Section: Metabolitementioning

confidence: 90%

Metabolomic screening of regional brain alterations in the APP/PS1 transgenic model of Alzheimer's disease by direct infusion mass spectrometry

González‐Domínguez

García-Barrera

Vitórica

et al. 2015

Journal of Pharmaceutical and Biomedical Analysis

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The identification of pathological mechanisms underlying to Alzheimer's disease is of great importance for the discovery of potential markers for diagnosis and disease monitoring. In this study, we investigated regional metabolic alterations in brain from the APP/PS1 mice, a transgenic model that reproduces well some of the neuropathological and cognitive deficits observed in human Alzheimer's disease. For this purpose, hippocampus, cortex, cerebellum and olfactory bulbs were analyzed using a high-throughput metabolomic approach based on direct infusion mass spectrometry. Metabolic fingerprints showed significant differences between transgenic and wild-type mice in all brain tissues, being hippocampus and cortex the most affected regions. Alterations in numerous metabolites were detected including phospholipids, fatty acids, purine and pyrimidine metabolites, acylcarnitines, sterols and amino acids, among others. Furthermore, metabolic pathway analysis revealed important alterations in homeostasis of lipids, energy management, and metabolism of amino acids and nucleotides. Therefore, these findings demonstrate the potential of metabolomic screening and the use of transgenic models for understanding pathogenesis of Alzheimer's disease.

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Is the Urea Cycle Involved in Alzheimer's Disease?

Cited by 71 publications

References 36 publications

Metabolomic research on the role of interleukin-4 in Alzheimer’s disease

Metabolomic research on the role of interleukin-4 in Alzheimer’s disease

Application of metabolomics based on direct mass spectrometry analysis for the elucidation of altered metabolic pathways in serum from the APP/PS1 transgenic model of Alzheimer's disease

Metabolomic screening of regional brain alterations in the APP/PS1 transgenic model of Alzheimer's disease by direct infusion mass spectrometry

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