{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T16:47:24Z","timestamp":1772210844767,"version":"3.50.1"},"reference-count":32,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T00:00:00Z","timestamp":1620604800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The development of effective therapies as well as early, molecular diagnosis of Alzheimer\u2019s disease is impeded by the lack of understanding of the underlying pathological mechanisms. Metabolomics studies of body fluids as well as brain tissues have shown major changes in metabolic profiles of Alzheimer\u2019s patients. However, with analysis performed at the late stages of the disease it is not possible to distinguish causes and consequence. The mouse model APP\/PS1 expresses a mutant amyloid precursor protein resulting in early Amyloid \u03b2 (A\u03b2) accumulation as well as many resulting physiological changes including changes in metabolic profile and metabolism. Analysis of metabolic profile of cerebrospinal fluid (CSF) and blood of APP\/PS1 mouse model can provide information about metabolic changes in these body fluids caused by A\u03b2 accumulation. Using our novel method for analysis of correlation and mathematical ranking of significant correlations between metabolites in CSF and blood, we have explored changes in metabolite correlation and connectedness in APP\/PS1 and wild type mice. Metabolites concentration and correlation changes in CSF, blood and across the blood brain barrier determined in this work are affected by the production of amyloid plaque. Metabolite changes observed in the APP\/PS1 mouse model are the response to the mutation causing plaque formation, not the cause for the plaque suggesting that they are less relevant in the context of early treatment and prevention then the metabolic changes observed only in humans.<\/jats:p>","DOI":"10.1371\/journal.pone.0250568","type":"journal-article","created":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T14:50:27Z","timestamp":1620658227000},"page":"e0250568","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["NMR analysis of the correlation of metabolic changes in blood and cerebrospinal fluid in Alzheimer model male and female mice"],"prefix":"10.1371","volume":"16","author":[{"given":"Filip","family":"Stojanovic","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariam","family":"Taktek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nam Huan","family":"Khieu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junzhou","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kerry","family":"Rennie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Balu","family":"Chakravarthy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7476-6450","authenticated-orcid":true,"given":"Will J.","family":"Costain","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9483-8159","authenticated-orcid":true,"given":"Miroslava","family":"Cuperlovic-Culf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,5,10]]},"reference":[{"key":"pone.0250568.ref001","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/nrneurol.2011.2","article-title":"Epidemiology of Alzheimer disease","volume":"7","author":"C. Reitz","year":"2011","journal-title":"Nature Reviews Neurology"},{"key":"pone.0250568.ref002","first-page":"2","article-title":"Amino Acid Catabolism in Alzheimer\u2019s Disease Brain: Friend or Foe?","volume":"2017","author":"J. W. D. Griffin","year":"2003","journal-title":"Oxidative Medicine and Cellular Longevity"},{"key":"pone.0250568.ref003","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.neurobiolaging.2014.08.004","article-title":"Deregulation of purine metabolism in Alzheimer\u2019s disease","volume":"36","author":"B. Ansoleaga","year":"2015","journal-title":"Neurobiol. Aging"},{"key":"pone.0250568.ref004","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.tem.2010.05.005","article-title":"Alzheimer\u2019s disease: Brain expression of a metabolic disorder?","volume":"21","author":"S. Merlo","year":"2010","journal-title":"Trends in Endocrinology and Metabolism"},{"issue":"5","key":"pone.0250568.ref005","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0063644","article-title":"Identification of Altered Metabolic Pathways in Plasma and CSF in Mild Cognitive Impairment and Alzheimer\u2019s Disease Using Metabolomics","volume":"8","author":"E. Trushina","year":"2013","journal-title":"PLoS One"},{"key":"pone.0250568.ref006","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pmed.1002266","article-title":"Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance: A nontargeted metabolomic study","volume":"14","author":"S. G. Snowden","year":"2017","journal-title":"PLoS Med."},{"key":"pone.0250568.ref007","article-title":"Recent Advances from Metabolomics and Lipidomics Application in Alzheimer\u2019s Disease Inspiring Drug Discovery","author":"M. Cuperlovic-Culf","year":"2019","journal-title":"Exp. Op Drug Discovery"},{"issue":"2","key":"pone.0250568.ref008","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.jalz.2018.08.012","article-title":"Altered bile acid profile in mild cognitive impairment and Alzheimer\u2019s disease: Relationship to neuroimaging and CSF biomarkers","volume":"15","author":"K. Nho","year":"2019","journal-title":"Alzheimer\u2019s and Dementia"},{"issue":"5","key":"pone.0250568.ref009","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0063644","article-title":"Identification of Altered Metabolic Pathways in Plasma and CSF in Mild Cognitive Impairment and Alzheimer\u2019s Disease Using Metabolomics","volume":"8","author":"E. Trushina","year":"2013","journal-title":"PLoS ONE"},{"key":"pone.0250568.ref010","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pmed.1002482","article-title":"Brain and blood metabolite signatures of pathology and progression in Alzheimer disease: A targeted metabolomics study","volume":"15","author":"V. R. Varma","year":"2018","journal-title":"PLOS Medicine"},{"issue":"3","key":"pone.0250568.ref011","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/metabo8030052","article-title":"High-throughput direct mass spectrometry-based metabolomics to characterize metabolite fingerprints associated with Alzheimer\u2019s disease pathogenesis","volume":"8","author":"R. Gonz\u00e1lez-Dom\u00ednguez","year":"2018","journal-title":"Metabolites"},{"issue":"9","key":"pone.0250568.ref012","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/j.jalz.2017.01.020","article-title":"Metabolic network failures in Alzheimer\u2019s disease: A biochemical road map","volume":"13","author":"J. B. Toledo","year":"2017","journal-title":"Alzheimer\u2019s and Dementia"},{"key":"pone.0250568.ref013","first-page":"97","article-title":"Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes","author":"L. Holcomb","year":"1998","journal-title":"Nature"},{"key":"pone.0250568.ref014","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1063\/1.1716296","article-title":"Modified spin-echo method for measuring nuclear relaxation times","volume":"29","author":"S. Meiboom","year":"1958","journal-title":"Rev. Sci. Instrum."},{"issue":"3","key":"pone.0250568.ref015","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.bbrc.2008.08.007","article-title":"A multi-metabolite analysis of serum by 1H NMR spectroscopy: Early systemic signs of Alzheimer\u2019s disease","volume":"375","author":"T. Tukiainen","year":"2008","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"pone.0250568.ref016","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1039\/b910205a","article-title":"High-throughput serum NMR metabonomics for cost-effective holistic studies on systemic metabolism","volume":"134","author":"P. Soininen","year":"2009","journal-title":"Analyst"},{"issue":"1","key":"pone.0250568.ref017","doi-asserted-by":"crossref","first-page":"e73","DOI":"10.1212\/WNL.0000000000004749","article-title":"Increased midlife triglycerides predict brain \u03b2-amyloid and tau pathology 20 years later","volume":"90","author":"K. N\u00e4gga","year":"2018","journal-title":"Neurology"},{"issue":"51","key":"pone.0250568.ref018","doi-asserted-by":"crossref","first-page":"32916","DOI":"10.1074\/jbc.271.51.32916","article-title":"Amyloid \u03b2-peptide is transported on lipoproteins and albumin in human plasma","volume":"271","author":"A. L. Biere","year":"1996","journal-title":"Journal of Biological Chemistry"},{"issue":"1","key":"pone.0250568.ref019","first-page":"1","article-title":"Blood-brain barrier-associated pericytes internalize and clear aggregated amyloid-\u03b242 by LRP1-dependent apolipoprotein e isoform-specific mechanism","volume":"13","author":"Q. Ma","year":"2018","journal-title":"Molecular Neurodegeneration"},{"key":"pone.0250568.ref020","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1258\/acb.2008.007214","article-title":"Wiltfang, Plasma lipoprotein beta-amyloid in subjects with Alzheimer\u2019s disease or mild cognitive impairment","volume":"45","author":"J.C. Mamo","year":"2008","journal-title":"J. Ann Clin Biochem"},{"key":"pone.0250568.ref021","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1038\/sj.jcbfm.9600419","article-title":"Transport pathways for clearance of human Alzheimer\u2019s amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system","volume":"27","author":"RD Bell","year":"2007","journal-title":"J Cereb Blood Flow Metab"},{"key":"pone.0250568.ref022","doi-asserted-by":"crossref","first-page":"7234","DOI":"10.1007\/s12035-019-1594-2","article-title":"LRP1 Has a Predominant Role in Production over Clearance of A\u03b2 in a Mouse Model of Alzheimer\u2019s Disease","volume":"56","author":"B. Van Gool","year":"2019","journal-title":"Mol Neurobiol"},{"issue":"24","key":"pone.0250568.ref023","doi-asserted-by":"crossref","first-page":"20164","DOI":"10.1074\/jbc.M111.337196","article-title":"1H NMR metabolomics analysis of glioblastoma subtypes: correlation between metabolomics and gene expression characteristics","volume":"287","author":"M. Cuperlovic-Culf","year":"2012","journal-title":"Journal of Biological Chemistry"},{"issue":"10","key":"pone.0250568.ref024","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/s11306-017-1244-5","article-title":"ASICS: an automatic method for identification and quantification of metabolites in complex 1D 1H NMR spectra","volume":"13","author":"P. J. C. P. J. C. Tardivel","year":"2017","journal-title":"Metabolomics"},{"key":"pone.0250568.ref025","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1186\/1471-2105-12-400","article-title":"MetaboHunter: an automatic approach for identification of metabolites from 1H-NMR spectra of complex mixtures","volume":"12","author":"D. Tulpan","year":"2011","journal-title":"BMC Bioinformatics"},{"issue":"D1","key":"pone.0250568.ref026","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1093\/nar\/gks1065","article-title":"HMDB 3.0-The Human Metabolome Database in 2013","volume":"41","author":"D. S. Wishart","year":"2013","journal-title":"Nucleic Acids Research"},{"key":"pone.0250568.ref027","first-page":"157","article-title":"New bioinformatics resources for metabolomics. Pacific Symposium on Biocomputing","volume":"168","author":"J. L. Markley","year":"2007","journal-title":"cific Symposium on Biocomputing"},{"issue":"1","key":"pone.0250568.ref028","first-page":"154","article-title":"Wide-ranging alterations in the brain fatty acid complement of subjects with late Alzheimer\u2019s disease as detected by GC-MS","volume":"8","author":"M. L. Nasaruddin","year":"2016","journal-title":"American Journal of Translational Research"},{"key":"pone.0250568.ref029","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.neurobiolaging.2015.11.014","article-title":"Alzheimer\u2019s disease-like pathology has transient effects on the brain and blood metabolome","volume":"38","author":"X. Pan","year":"2016","journal-title":"Neurobiology of Aging"},{"issue":"2","key":"pone.0250568.ref030","doi-asserted-by":"crossref","first-page":"561","DOI":"10.3233\/JAD-171042","article-title":"Homocysteine and Dementia: An International Consensus Statement","volume":"62","author":"A. D. Smith","year":"2018","journal-title":"Journal of Alzheimer\u2019s Disease"},{"issue":"17","key":"pone.0250568.ref031","doi-asserted-by":"crossref","first-page":"5655","DOI":"10.1021\/ac050619p","article-title":"Application of fast Fourier transform cross-correlation for the alignment of large chromatographic and spectral dataset","volume":"77","author":"J.W.H. Wong","journal-title":"Analytical chemistry"},{"issue":"2","key":"pone.0250568.ref032","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.jmr.2009.11.012","article-title":"icoshift: a versatile tool for the rapid alignment of 1D NMR spectra","volume":"202","author":"F. Savorani","year":"2010","journal-title":"Journal of Magnetic Resonance"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0250568","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T14:51:27Z","timestamp":1620658287000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0250568"}},"subtitle":[],"editor":[{"given":"Stephen D.","family":"Ginsberg","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,5,10]]},"references-count":32,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5,10]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0250568","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.05.26.116525","asserted-by":"object"}]},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,10]]}}}