Regional metabolic alteration of Alzheimer's disease in mouse brain expressing mutant human APP-PS1 by 1H HR-MAS☆

Woo, Dong‐Cheol; Lee, Sungho; Lee, Do-Wan; Kim, Sang-Young; Kim, Goo-Young; Rhim, Hyangshuk; Choi, Chi-Bong; Kim, Hwi-Yool; Lee, Chang-Uk; Choe, Bo-Young

doi:10.1016/j.bbr.2010.03.026

Cited by 42 publications

(22 citation statements)

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“…Major differences were observed in cortex and hippocampus, but these impairments also affected other regions such as cerebellum and olfactory bulbs. Furthermore, it is also noteworthy the great number of discriminant metabolites detected with this high-throughput tool compared with previous studies based on NMR [11][12][13], facilitating the elucidation of potential mechanisms underlying to pathology.…”

Section: Discussionmentioning

confidence: 94%

“…However, the characterization of regional metabolomic perturbations instead of overall brain changes may be of greater interest in order to investigate the impact of disease on different brain regions and determine the most affected ones in AD-mice. In this sense, only a few authors have previously performed a comparative metabolomic study in different brain regions using NMR, demonstrating that the hippocampus and temporal cortex are the most sensitive regions to disease, but other tissues are also affected such as cerebellum and midbrain [11][12][13]. Nevertheless, only medium to high abundance metabolites are detected with this approach and the identification of individual metabolites is challenging in complex mixtures, so very limited metabolic information can be obtained [14].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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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“…Thus, the most important disturbances could be related to dyshomeostasis of different amino acids, such as altered biosynthesis of phenylalanine, tyrosine and tryptophan (a), and abnormal metabolism of histidine (b), tyrosine (c), alanine, aspartate and glutamate (d), arginine and proline (f), as well as perturbed arachidonic acid metabolism (e). (Hu et al, 2012;, CRND8 (Salek et al, 2010;Lin et al, 2013;Lin et al, 2014), APP/PS1 M146L (Woo et al, 2010;Trushina et al, 2012), APP Tg2576 Lalande et al, 2014) or SAMP8 (Jiang et al, 2008;Wang et al, 2014), among others. Thereby, multiple associations have been described between Alzheimer's disease and metabolic perturbations such as oxidative stress, mitochondrial dysfunction, abnormal lipid metabolism or inflammatory processes.…”

Section: Resultsmentioning

confidence: 99%

“…1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Numerous efforts have been made in the last years to identify metabolic failures associated with pathological mechanisms underlying to Alzheimer's disease. To this end, different authors have previously addressed the metabolomic investigation of several mouse models of AD using both brain tissue and blood samples, such as theG APP/PS1 E9 (González-Domínguez et al 2014b;2015a), TASTPM (Hu et al, 2012;, CRND8 (Salek et al, 2010;Lin et al, 2013;Lin et al, 2014), APP/PS1 M146L (Woo et al, 2010;Trushina et al, 2012), APP Tg2576 Lalande et al, 2014) or SAMP8 (Jiang et al, 2008;Wang et al, 2014), among others. Thereby, multiple associations have been described between Alzheimer's disease and metabolic perturbations such as oxidative stress, mitochondrial dysfunction, abnormal lipid metabolism or inflammatory processes.…”

Section: Resultsmentioning

confidence: 99%

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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“…A diagnostic test based on the decreased levels of NAA and glutamate in APP Â PS2 mice brains was able to classify 'AD like' mice from normal mice with 92% sensitivity and 82% specificity (von Kienlin et al, 2005). In addition to decreased levels of NAA and glutamate, these studies have also reported myo-inositol (m-In) content elevated in APP and PS1 mouse cerebrums (Marjanska et al, 2005;Woo et al, 2010;Forster et al, 2012). M-In is predominantly expressed in glial cells compared to neurons; its levels are considered to be indicative of osmotic stress and astroglosis (Castillo et al, 2000).…”

Section: Animal Models Of Admentioning

confidence: 99%

Small molecule biomarkers in Alzheimer’s disease

Kim

Legido‐Quigley

2018

OCL

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-Alzheimer's disease (AD) is a progressive neurodegenerative disease which affects a growing number of people as the population ages worldwide. Alzheimer's Disease International estimated that more than 100 million people will be living with dementia by 2050. At present there are no disease-modifying therapies and research has expanded to the Àomic sciences with scientists aiming to get a holistic view of the disease using systems medicine. Metabolomics and Lipidomics give a snap-shot of the metabolism. As analyzing the brain in vivo is difficult, the metabolic information of the periphery has potential to unravel mechanisms that have not been considered, such as those that link the brain to the liver and the gut or other organs. With that in mind we have produced a mini-review, to record a number of studies in the field and the molecular pathways that have been flagged in animal and human models of AD. Human studies deal with cohorts in the order of the hundreds due to the difficulty of organizing AD studies, however it is possible that these first pilots point towards important mechanisms. The trend in these small studies is the involvement of many organs and pathways. Some findings, that have been reproduced, are ceramides being increased, phospholipids and neurotransmitters depleted and sterols being found depleted too. Initial findings point to an important role to lipid homeostasis in AD, this is not surprising as the brain's main constituents are water and lipids.Keywords: Alzheimer's disease / metabolomics / lipidomics / biomarker Résumé -Biomarqueurs à petites molécules dans la maladie d'Alzheimer. La maladie d'Alzheimer est une maladie neurodégénérative progressive qui affecte un nombre croissant de personnes en raison du vieillissement de la population observé dans le monde entier. La fédération internationale d'associations Alzheimer's disease International estime que plus de 100 millions de personnes vivront avec cette démence d'ici à 2050. Il n'existe actuellement aucun traitement de la maladie et la recherche s'est élargie aux sciences -omiques avec l'objectif scientifique d'obtenir une approche globale de la maladie en utilisant une médecine des systèmes. La métabolomique et la lipidomique donnent un aperçu du métabolisme. L'analyse du cerveau in vivo s'avérant difficile, l'information métabolique de la périphérie possède le potentiel de démêler des mécanismes qui n'ont pas été pris en compte, tels que ceux reliant le cerveau au foie et à l'intestin ou à d'autres organes. Dans cet esprit, nous proposons une mini-revue, afin de lister un certain nombre d'études relevant de ce champ et les voies moléculaires qui ont été signalées chez les modèles animaux et humains de la maladie d'Alzheimer. Les études humaines traitent des cohortes de quelque centaines d'individus en raison de la difficulté à organiser des études sur cette pathologie, mais il est possible que ces premiers pilotes pointent vers des mécanismes importants. La tendance dans ces petites études est l'implication de nombreux org...

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Regional metabolic alteration of Alzheimer's disease in mouse brain expressing mutant human APP-PS1 by 1H HR-MAS☆

Cited by 42 publications

References 46 publications

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

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

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

Small molecule biomarkers in Alzheimer’s disease

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