{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T21:20:36Z","timestamp":1793481636260,"version":"4.5.0"},"reference-count":139,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2020,2,11]],"date-time":"2020-02-11T00:00:00Z","timestamp":1581379200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,2,11]],"date-time":"2020-02-11T00:00:00Z","timestamp":1581379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Biogerontology"],"published-print":{"date-parts":[[2020,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Alzheimer\u2019s disease (AD) is a debilitating neurodegenerative disease that causes a progressive decline in memory, language and problem solving. For decades mechanism-based therapies have primarily focused on amyloid \u03b2 (A\u03b2) processing and pathways that govern neurofibrillary tangle generation. With the potential exception to Aducanumab, a monotherapy to target A\u03b2, clinical trials in these areas have been challenging and have failed to demonstrate efficacy. Currently, the prescribed therapies for AD are those that target the cholinesterase and glutamatergic systems that can moderately reduce cognitive decline, dependent on the individual. In the brain, over 40% of neuronal synapses are glutamatergic, where the glutamate level is tightly regulated through metabolite exchange in neuronal, astrocytic and endothelial cells. In AD brain, A\u03b2 can interrupt effective glutamate uptake by astrocytes, which evokes a cascade of events that leads to neuronal swelling, destruction of membrane integrity and ultimately cell death. Much work has focussed on the post-synaptic response with little insight into how glutamate is regulated more broadly in the brain and the influence of anaplerotic pathways that finely tune these mechanisms. The role of blood branched chain amino acids (BCAA) in regulating neurotransmitter profiles under disease conditions also warrant discussion. Here, we review the importance of the branched chain aminotransferase proteins in regulating brain glutamate and the potential consequence of dysregulated metabolism in the context of BCAA or glutamate accumulation. We explore how the reported benefits of BCAA supplementation or restriction in improving cognitive function in other neurological diseases may have potential application in AD. Given that memantine, the glutamate receptor agonist, shows clinical relevance it is now timely to research related pathways, an understanding of which could identify novel approaches to treatment of AD.<\/jats:p>","DOI":"10.1007\/s10522-020-09860-4","type":"journal-article","created":{"date-parts":[[2020,2,11]],"date-time":"2020-02-11T20:15:47Z","timestamp":1581452147000},"page":"257-274","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":172,"title":["Alzheimer\u2019s disease: targeting the glutamatergic system"],"prefix":"10.1007","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6801-7245","authenticated-orcid":false,"given":"Myra E.","family":"Conway","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,2,11]]},"reference":[{"issue":"4","key":"9860_CR1","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1212\/WNL.42.4.733","volume":"42","author":"RL Albin","year":"1992","unstructured":"Albin RL, Greenamyre JT (1992) Alternative excitotoxic hypotheses. Neurology 42(4):733\u2013738","journal-title":"Neurology"},{"issue":"6","key":"9860_CR2","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1212\/WNL.56.6.737","volume":"56","author":"PG Antuono","year":"2001","unstructured":"Antuono PG, Jones JL, Wang Y, Li SJ (2001) Decreased glutamate+glutamine in Alzheimer's disease detected in vivo with (1)H-MRS at 0.5 T. Neurology 56(6):737\u2013742","journal-title":"Neurology"},{"issue":"9","key":"9860_CR3","doi-asserted-by":"publisher","first-page":"1642","DOI":"10.1016\/j.apmr.2008.02.023","volume":"89","author":"R Aquilani","year":"2008","unstructured":"Aquilani R, Boselli M, Boschi F, Viglio S, Iadarola P, Dossena M, Pastoris O, Verri M (2008a) Branched-chain amino acids may improve recovery from a vegetative or minimally conscious state in patients with traumatic brain injury: a pilot study. Arch Phys Med Rehabil 89(9):1642\u20131647","journal-title":"Arch Phys Med Rehabil"},{"issue":"12","key":"9860_CR4","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.1177\/0269215508094244","volume":"22","author":"R Aquilani","year":"2008","unstructured":"Aquilani R, Scocchi M, Iadarola P, Franciscone P, Verri M, Boschi F, Pasini E, Viglio S (2008b) Protein supplementation may enhance the spontaneous recovery of neurological alterations in patients with ischaemic stroke. Clin Rehabil 22(12):1042\u20131050","journal-title":"Clin Rehabil"},{"issue":"1","key":"9860_CR5","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1007\/s11064-016-1855-7","volume":"42","author":"EL Ashby","year":"2017","unstructured":"Ashby EL, Kierzkowska M, Hull J, Kehoe PG, Hutson SM, Conway ME (2017) Altered expression of human mitochondrial branched chain aminotransferase in dementia with lewy bodies and vascular dementia. Neurochem Res 42(1):306\u2013319","journal-title":"Neurochem Res"},{"issue":"4","key":"9860_CR6","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1016\/j.jalz.2016.03.001","volume":"12","author":"A Association","year":"2016","unstructured":"Association A (2016) 2016 Alzheimer's disease facts and figures. Alzheimers Dement 12(4):459\u2013509","journal-title":"Alzheimers Dement"},{"issue":"6","key":"9860_CR7","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1016\/j.clinbiochem.2008.12.005","volume":"42","author":"AG Barschak","year":"2009","unstructured":"Barschak AG, Sitta A, Deon M, Busanello EN, Coelho DM, Cipriani F, Dutra-Filho CS, Giugliani R, Wajner M, Vargas CR (2009) Amino acids levels and lipid peroxidation in maple syrup urine disease patients. Clin Biochem 42(6):462\u2013466","journal-title":"Clin Biochem"},{"key":"9860_CR8","doi-asserted-by":"publisher","first-page":"304","DOI":"10.3389\/fnins.2019.00304","volume":"13","author":"A Benussi","year":"2019","unstructured":"Benussi A, Alberici A, Buratti E, Ghidoni R, Gardoni F, Di Luca M, Padovani A, Borroni B (2019) Toward a glutamate hypothesis of frontotemporal dementia. Front Neurosci 13:304","journal-title":"Front Neurosci"},{"issue":"5","key":"9860_CR9","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1177\/002215549704500506","volume":"45","author":"MG Bixel","year":"1997","unstructured":"Bixel MG, Hutson SM, Hamprecht B (1997) Cellular distribution of branched-chain amino acid aminotransferase isoenzymes among rat brain glial cells in culture. J Histochem Cytochem 45(5):685\u2013694","journal-title":"J Histochem Cytochem"},{"issue":"3","key":"9860_CR10","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1177\/002215540104900314","volume":"49","author":"M Bixel","year":"2001","unstructured":"Bixel M, Shimomura Y, Hutson S, Hamprecht B (2001) Distribution of key enzymes of branched-chain amino acid metabolism in glial and neuronal cells in culture. J Histochem Cytochem 49(3):407\u2013418","journal-title":"J Histochem Cytochem"},{"issue":"7","key":"9860_CR11","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1056\/NEJM200008173430701","volume":"343","author":"SY Bookheimer","year":"2000","unstructured":"Bookheimer SY, Strojwas MH, Cohen MS, Saunders AM, Pericak-Vance MA, Mazziotta JC, Small GW (2000) Patterns of brain activation in people at risk for Alzheimer's disease. N Engl J Med 343(7):450\u2013456","journal-title":"N Engl J Med"},{"issue":"6403","key":"9860_CR12","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1038\/360471a0","volume":"360","author":"M Bouvier","year":"1992","unstructured":"Bouvier M, Szatkowski M, Amato A, Attwell D (1992) The glial cell glutamate uptake carrier counter transports pH-changing anions. Nature 360(6403):471\u2013474","journal-title":"Nature"},{"issue":"1","key":"9860_CR13","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/0304-4165(81)90153-7","volume":"677","author":"K Brand","year":"1981","unstructured":"Brand K (1981) Metabolism of 2-oxoacid analogues of leucine, valine and phenylalanine by heart muscle, brain and kidney of the rat. Biochim Biophys Acta 677(1):126\u2013132","journal-title":"Biochim Biophys Acta"},{"issue":"4","key":"9860_CR14","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1515\/bchm2.1984.365.1.463","volume":"365","author":"K Brand","year":"1984","unstructured":"Brand K, Hauschildt S (1984) Metabolism of 2-oxo-acid analogues of leucine and valine in isolated rat hepatocytes. Hoppe Seylers Z Physiol Chem 365(4):463\u2013468","journal-title":"Hoppe Seylers Z Physiol Chem"},{"key":"9860_CR15","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1002\/cne.10760","volume":"463","author":"T Bussiere","year":"2003","unstructured":"Bussiere T, Giannakopoulos P, Bouras C, Perl DP, Morrison JH, Hof PR (2003) Progressive degeneration of nonphosphorylated neurofilament protein-enriched pyramidal neurons predicts cognitive impairment in Alzheimer\u2019s disease: stereologic analysis of prefrontal cortex area 9. J Comp Neurol 463:281\u2013382","journal-title":"J Comp Neurol"},{"issue":"5","key":"9860_CR16","doi-asserted-by":"publisher","first-page":"307","DOI":"10.3109\/00207454.2013.833510","volume":"124","author":"Z Cai","year":"2014","unstructured":"Cai Z, Hussain MD, Yan LJ (2014) Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer's disease. Int J Neurosci 124(5):307\u2013321","journal-title":"Int J Neurosci"},{"issue":"1","key":"9860_CR17","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.brainres.2006.06.012","volume":"1108","author":"S Castellano","year":"2006","unstructured":"Castellano S, Macchi F, Scali M, Huang JZ, Bozzi Y (2006) Cytosolic branched chain aminotransferase (BCATc) mRNA is up-regulated in restricted brain areas of BDNF transgenic mice. Brain Res 1108(1):12\u201318","journal-title":"Brain Res"},{"issue":"4","key":"9860_CR18","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1016\/j.modgep.2006.10.010","volume":"7","author":"S Castellano","year":"2007","unstructured":"Castellano S, Casarosa S, Sweatt AJ, Hutson SM, Bozzi Y (2007) Expression of cytosolic branched chain aminotransferase (BCATc) mRNA in the developing mouse brain. Gene Expr Patterns 7(4):485\u2013490","journal-title":"Gene Expr Patterns"},{"key":"9860_CR19","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1126\/science.663662","volume":"201","author":"PH Chan","year":"1978","unstructured":"Chan PH, Fishman RA (1978) Brain edema: induction in cortical slices by polyunsaturated fatty acids. Science 201:358\u2013360","journal-title":"Science"},{"issue":"4","key":"9860_CR20","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1111\/j.1471-4159.1976.tb04440.x","volume":"26","author":"ER Chaplin","year":"1976","unstructured":"Chaplin ER, Goldberg AL, Diamond I (1976) Leucine oxidation in brain slices and nerve endings. J Neurochem 26(4):701\u2013707","journal-title":"J Neurochem"},{"issue":"3","key":"9860_CR21","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1016\/0896-6273(95)90158-2","volume":"15","author":"FA Chaudhry","year":"1995","unstructured":"Chaudhry FA, Lehre KP, van Lookeren Campagne M, Ottersen OP, Danbolt NC, Storm-Mathisen J (1995) Glutamate transporters in glial plasma membranes: highly differentiated localizations revealed by quantitative ultrastructural immunocytochemistry. Neuron 15(3):711\u2013720","journal-title":"Neuron"},{"issue":"2","key":"9860_CR22","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1523\/JNEUROSCI.07-02-00357.1987","volume":"7","author":"DW Choi","year":"1987","unstructured":"Choi DW, Maulucci-Gedde M (1987) Kriegstein AR Glutamate neurotoxicity in cortical cell culture. J Neurosci 7(2):357\u2013368","journal-title":"J Neurosci"},{"key":"9860_CR23","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/S0076-6879(00)24250-X","volume":"324","author":"JL Chuang","year":"2000","unstructured":"Chuang JL, Chuang DT (2000) Diagnosis and mutational analysis of maple syrup urine disease using cell cultures. Methods Enzymol 324:413\u2013423","journal-title":"Methods Enzymol"},{"issue":"1 Suppl","key":"9860_CR24","doi-asserted-by":"publisher","first-page":"243S","DOI":"10.1093\/jn\/136.1.243S","volume":"136","author":"DT Chuang","year":"2006","unstructured":"Chuang DT, Chuang JL, Wynn RM (2006) Lessons from genetic disorders of branched-chain amino acid metabolism. J Nutr 136(1 Suppl):243S\u2013S249","journal-title":"J Nutr"},{"key":"9860_CR25","doi-asserted-by":"publisher","first-page":"1498","DOI":"10.1126\/science.1359647","volume":"258","author":"JD Clements","year":"1992","unstructured":"Clements JD, Lester RA, Tong G, Jahr CE, Westbrook GL (1992) The time course of glutamate in the synaptic cleft. Science 258:1498\u20131501","journal-title":"Science"},{"issue":"1","key":"9860_CR26","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1073\/pnas.0910280107","volume":"107","author":"JT Cole","year":"2010","unstructured":"Cole JT, Mitala CM, Kundu S, Verma A, Elkind JA, Nissim I, Cohen AS (2010) Dietary branched chain amino acids ameliorate injury-induced cognitive impairment. Proc Natl Acad Sci USA 107(1):366\u2013371","journal-title":"Proc Natl Acad Sci USA"},{"key":"9860_CR27","first-page":"143","volume":"40","author":"GL Collingridge","year":"1989","unstructured":"Collingridge GL, Lester RAJ (1989) Excitatory amino acid receptors in the vertebrate central nervous system. Pharmacol Rev 40:143\u2013210","journal-title":"Pharmacol Rev"},{"key":"9860_CR28","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1007\/978-3-319-45096-4_5","volume":"13","author":"ME Conway","year":"2016","unstructured":"Conway ME, Hutson SM (2016) BCAA metabolism and NH(3) homeostasis. Adv Neurobiol 13:99\u2013132","journal-title":"Adv Neurobiol"},{"issue":"29","key":"9860_CR29","doi-asserted-by":"publisher","first-page":"9070","DOI":"10.1021\/bi020200i","volume":"41","author":"ME Conway","year":"2002","unstructured":"Conway ME, Yennawar N, Wallin R, Poole LB, Hutson SM (2002) Identification of a peroxide-sensitive redox switch at the CXXC motif in the human mitochondrial branched chain aminotransferase. Biochemistry 41(29):9070\u20139078","journal-title":"Biochemistry"},{"issue":"23","key":"9860_CR30","doi-asserted-by":"publisher","first-page":"7356","DOI":"10.1021\/bi0498050","volume":"43","author":"ME Conway","year":"2004","unstructured":"Conway ME, Poole LB, Hutson SM (2004) Roles for cysteine residues in the regulatory CXXC motif of human mitochondrial branched chain aminotransferase enzyme. Biochemistry 43(23):7356\u20137364","journal-title":"Biochemistry"},{"issue":"19","key":"9860_CR31","doi-asserted-by":"publisher","first-page":"5465","DOI":"10.1021\/bi800303h","volume":"47","author":"ME Conway","year":"2008","unstructured":"Conway ME, Coles SJ, Islam MM, Hutson SM (2008) Regulatory control of human cytosolic branched-chain aminotransferase by oxidation and S-glutathionylation and its interactions with redox sensitive neuronal proteins. Biochemistry 47(19):5465\u20135479","journal-title":"Biochemistry"},{"issue":"2","key":"9860_CR32","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1176\/appi.neuropsych.12050115","volume":"25","author":"C Cooney","year":"2013","unstructured":"Cooney C, Murphy S, Tessema H, Freyne A (2013) Use of low-dose gabapentin for aggressive behavior in vascular and Mixed Vascular\/Alzheimer Dementia. J Neuropsychiatry Clin Neurosci 25(2):120\u2013125","journal-title":"J Neuropsychiatry Clin Neurosci"},{"issue":"4S Suppl","key":"9860_CR33","doi-asserted-by":"publisher","first-page":"1026S","DOI":"10.1093\/jn\/130.4.1026S","volume":"130","author":"Y Daikhin","year":"2000","unstructured":"Daikhin Y, Yudkoff M (1026S) Compartmentation of brain glutamate metabolism in neurons and glia. J Nutr 130(4S Suppl):1026S\u2013S1031","journal-title":"J Nutr"},{"issue":"1","key":"9860_CR34","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0301-0082(00)00067-8","volume":"65","author":"NC Danbolt","year":"2001","unstructured":"Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65(1):1\u2013105","journal-title":"Prog Neurobiol"},{"key":"9860_CR35","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1542\/peds.25.1.72","volume":"25","author":"J Dancis","year":"1960","unstructured":"Dancis J, Levitz M, Westall RG (1960) Maple syrup urine disease: branched-chain keto-aciduria. Pediatrics 25:72\u201379","journal-title":"Pediatrics"},{"issue":"9","key":"9860_CR36","doi-asserted-by":"publisher","first-page":"1424","DOI":"10.1016\/j.jmb.2017.03.018","volume":"429","author":"AR Duan","year":"2017","unstructured":"Duan AR, Jonasson EM, Alberico EO, Li C, Scripture JP, Miller RA, Alber MS, Goodson HV (2017) Interactions between Tau and different conformations of tubulin: implications for tau function and mechanism. J Mol Biol 429(9):1424\u20131438","journal-title":"J Mol Biol"},{"key":"9860_CR37","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1523\/JNEUROSCI.13-02-00623.1993","volume":"13","author":"JM Dubinsky","year":"1993","unstructured":"Dubinsky JM (1993) Intracellular calcium levels during the period of delayed excitotoxicity. J Neurosci 13:623\u2013631","journal-title":"J Neurosci"},{"issue":"16","key":"9860_CR38","doi-asserted-by":"publisher","first-page":"2497","DOI":"10.1089\/ars.2012.4869","volume":"20","author":"M El Hindy","year":"2014","unstructured":"El Hindy M, Hezwani M, Corry D, Hull J, El Amraoui F, Harris M, Lee C, Forshaw T, Wilson A, Mansbridge A, Hassler M, Patel VB, Kehoe PG, Love S, Conway ME (2014) The branched-chain aminotransferase proteins: novel redox chaperones for protein disulfide isomerase\u2013implications in Alzheimer's disease. Antioxid Redox Signal 20(16):2497\u20132513","journal-title":"Antioxid Redox Signal"},{"key":"9860_CR39","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1177\/1533317511421780","volume":"26","author":"N Fayed","year":"2011","unstructured":"Fayed N, Modrego PJ, Rojas-Salinas G, Aguilar K (2011) Brain glutamate levels are decreased in Alzheimer\u2019s disease: a magnetic resonance spectroscopy study. Am J Alzheimer\u2019s Dis Other Dement 26:450\u2013456","journal-title":"Am J Alzheimer\u2019s Dis Other Dement"},{"issue":"2","key":"9860_CR40","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1177\/1073858407308518","volume":"14","author":"DE Featherstone","year":"2008","unstructured":"Featherstone DE, Shippy SA (2008) Regulation of synaptic transmission by ambient extracellular glutamate. Neuroscientist 14(2):171\u2013181","journal-title":"Neuroscientist"},{"key":"9860_CR41","doi-asserted-by":"publisher","first-page":"1539S","DOI":"10.1093\/jn\/135.6.1539S","volume":"135","author":"J Fernstrom","year":"2005","unstructured":"Fernstrom J (2005) Branched-chain amino acids and brain function. J Nutr 135:1539S\u20131546S","journal-title":"J Nutr"},{"issue":"6 Suppl 1","key":"9860_CR42","doi-asserted-by":"publisher","first-page":"1539S","DOI":"10.1093\/jn\/137.6.1539S","volume":"137","author":"JD Fernstrom","year":"2007","unstructured":"Fernstrom JD, Fernstrom MH (1548S) Tyrosine, phenylalanine, and catecholamine synthesis and function in the brain. J Nutr 137(6 Suppl 1):1539S\u20131547S (discussion 1548S)","journal-title":"J Nutr"},{"issue":"1","key":"9860_CR43","doi-asserted-by":"publisher","first-page":"101","DOI":"10.2174\/1570159X13666150716165726","volume":"14","author":"TH Ferreira-Vieira","year":"2016","unstructured":"Ferreira-Vieira TH, Guimaraes IM, Silva FR, Ribeiro FM (2016) Alzheimer's disease: targeting the cholinergic system. Curr Neuropharmacol 14(1):101\u2013115","journal-title":"Curr Neuropharmacol"},{"issue":"7","key":"9860_CR44","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1016\/j.neuint.2006.05.007","volume":"49","author":"C Funchal","year":"2006","unstructured":"Funchal C, Latini A, Jacques-Silva MC, Dos Santos AQ, Buzin L, Gottfried C, Wajner M, Pessoa-Pureur R (2006) Morphological alterations and induction of oxidative stress in glial cells caused by the branched-chain alpha-keto acids accumulating in maple syrup urine disease. Neurochem Int 49(7):640\u2013650","journal-title":"Neurochem Int"},{"issue":"6","key":"9860_CR45","doi-asserted-by":"publisher","first-page":"2312","DOI":"10.1046\/j.1471-4159.1997.69062312.x","volume":"69","author":"WC Gamberino","year":"1997","unstructured":"Gamberino WC, Berkich DA, Lynch CJ, Xu B, LaNoue KF (1997) Role of pyruvate carboxylase in facilitation of synthesis of glutamate and glutamine in cultured astrocytes. J Neurochem 69(6):2312\u20132325","journal-title":"J Neurochem"},{"key":"9860_CR46","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.neuroimage.2013.04.012","volume":"78","author":"F Gao","year":"2013","unstructured":"Gao F, Edden RAE, Li M, Puts NAJ, Wang G, Liu C, Zhao B, Wang H, Bai X, Zhao C, Wang X, Barker PB (2013) Edited magnetic resonance spectroscopy detects an age-related decline in brain GABA levels. Neuroimage 78:75\u201382","journal-title":"Neuroimage"},{"issue":"6","key":"9860_CR47","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1111\/j.1471-4159.2006.04332.x","volume":"100","author":"MA Garc\u00eda-Espinosa","year":"2007","unstructured":"Garc\u00eda-Espinosa MA, Wallin R, Hutson SM, Sweatt AJ (2007) Widespread neuronal expression of branched-chain aminotransferase in the CNS: implications for leucine\/glutamate metabolism and for signaling by amino acids. J Neurochem 100(6):1458\u20131468","journal-title":"J Neurochem"},{"issue":"1","key":"9860_CR48","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1046\/j.1471-4159.2003.01972.x","volume":"87","author":"M Gottlieb","year":"2003","unstructured":"Gottlieb M, Wang Y, Teichberg VI (2003) Blood-mediated scavenging of cerebrospinal fluid glutamate. J Neurochem 87(1):119\u2013126","journal-title":"J Neurochem"},{"issue":"5","key":"9860_CR49","doi-asserted-by":"crossref","first-page":"3092","DOI":"10.1016\/S0021-9258(18)53663-2","volume":"268","author":"TR Hall","year":"1993","unstructured":"Hall TR, Wallin R, Reinhart GD et al (1993) Branched chain aminotransferase isoenzymes. Purification and characterization of the rat brain isoenzyme. J Biol Chem. 268(5):3092\u20133098","journal-title":"J Biol Chem."},{"key":"9860_CR50","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1007\/7854_2011_166","volume":"11","author":"H Hall","year":"2012","unstructured":"Hall H, Cuellar-Baena S, Dahlberg C, In't Zandt R, Denisov V, Kirik D (2012) Magnetic resonance spectroscopic methods for the assessment of metabolic functions in the diseased brain. Curr Top Behav Neurosci 11:169\u2013198","journal-title":"Curr Top Behav Neurosci"},{"issue":"2","key":"9860_CR51","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1016\/j.bbrc.2003.11.007","volume":"313","author":"RA Harris","year":"2004","unstructured":"Harris RA, Joshi M, Jeoung NH (2004) Mechanisms responsible for regulation of branched-chain amino acid catabolism. Biochem Biophys Res Commun 313(2):391\u2013396","journal-title":"Biochem Biophys Res Commun"},{"key":"9860_CR52","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2020.01.019","author":"M Harris","year":"2020","unstructured":"Harris M, El Hindy M, Usmari-Moraes M, Hudd F, Shafei M, Dong M, Hezwani M, Clark P, House M, Forshaw T, Kehoe P, Conway ME (2020) BCAT-induced autophagy regulates A\u03b2 load through an interdependence of redox state and PKC phosphorylation-implications in Alzheimer's disease. Free Radic Biol Med. https:\/\/doi.org\/10.1016\/j.freeradbiomed.2020.01.019","journal-title":"Free Radic Biol Med"},{"issue":"1","key":"9860_CR53","doi-asserted-by":"publisher","first-page":"337","DOI":"10.3233\/JAD-160041","volume":"53","author":"KN Hascup","year":"2016","unstructured":"Hascup KN, Hascup ER (2016) Soluble amyloid-\u03b242 stimulates glutamate release through activation of the \u03b17 nicotinic acetylcholine receptor. J Alzheimers Dis 53(1):337\u201347","journal-title":"J Alzheimers Dis"},{"key":"9860_CR139","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1002\/glia.22321","volume":"60","author":"HC Helms","year":"2012","unstructured":"Helms HC, Madelung R, Waagepetersen HS, Nielsen CU, Brodin B (2012) In vitro evidence for the brain glutamate efflux hypothesis: Brain endothelial cells cocultured with astrocytes display a polarized brain-to-blood transport of glutamate. Glia 60:882\u2013893","journal-title":"Glia"},{"key":"9860_CR136","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1007\/978-1-4939-9463-2_13","volume":"1990","author":"MEL Hindy","year":"2019","unstructured":"Hindy MEL, Conway ME (2019) Redox-regulated, targeted affinity isolation of NADH-dependent protein interactions with the branched chain aminotransferase proteins. Methods Mol Biol 1990:151\u2013163. https:\/\/doi.org\/10.1007\/978-1-4939-9463-2_13","journal-title":"Methods Mol Biol"},{"issue":"3","key":"9860_CR54","doi-asserted-by":"publisher","first-page":"1206","DOI":"10.1046\/j.1471-4159.1999.0731206.x","volume":"73","author":"K Hosoya","year":"1999","unstructured":"Hosoya K, Sugawara M, Asaba H, Terasaki T (1999) Blood-brain barrier produces significant efflux of L-aspartic acid but not D-aspartic acid: in vivo evidence using the brain efflux index method. J Neurochem 73(3):1206\u20131211","journal-title":"J Neurochem"},{"key":"9860_CR55","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.brainres.2017.10.011","volume":"1678","author":"S Huang","year":"2018","unstructured":"Huang S, Tong H, Lei M, Zhou M, Guo W, Li G, Tang X, Li Z, Mo M, Zhang X, Chen X, Cen L, Wei L, Xiao Y, Li K, Huang Q, Yang X, Liu W, Zhang L, Qu S, Li S, Xu P (2018) Astrocytic glutamatergic transporters are involved in A\u03b2-induced synaptic dysfunction. Brain Res 1678:129\u2013137","journal-title":"Brain Res"},{"issue":"3","key":"9860_CR56","doi-asserted-by":"publisher","first-page":"931","DOI":"10.3233\/JAD-180879","volume":"67","author":"F Hudd","year":"2019","unstructured":"Hudd F, Shiel A, Harris M, Bowdler P, McCann B, Tsivos D, Wearn A, Knight M, Kauppinen R, Coulthard E, White P, Conway ME (2019) Novel blood biomarkers that correlate with cognitive performance and hippocampal volumetry: potential for early diagnosis of alzheimer's disease. J Alzheimers Dis 67(3):931\u2013947","journal-title":"J Alzheimers Dis"},{"issue":"6","key":"9860_CR57","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1111\/jnc.12044","volume":"123","author":"J Hull","year":"2012","unstructured":"Hull J, Hindy ME, Kehoe PG, Chalmers K, Love S, Conway ME (2012) Distribution of the branched chain aminotransferase proteins in the human brain and their role in glutamate regulation. J Neurochem. 123(6):997\u20131009","journal-title":"J Neurochem."},{"issue":"3","key":"9860_CR58","doi-asserted-by":"publisher","first-page":"891","DOI":"10.3233\/JAD-142970","volume":"45","author":"J Hull","year":"2015","unstructured":"Hull J, Patel V, El-Hindy M, Lee C, Odeleye E, Hezwani M, Love S, Kehoe P, Chalmers K, Conway M (2015a) Regional increase in the expression of the bcat proteins in Alzheimer's disease brain: implications in glutamate toxicity. J Alzheimers Dis 45(3):891\u2013905","journal-title":"J Alzheimers Dis"},{"issue":"7","key":"9860_CR59","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1002\/jnr.23558","volume":"93","author":"J Hull","year":"2015","unstructured":"Hull J, Patel VB, Hutson SM, Conway ME (2015b) New insights into the role of the branched-chain aminotransferase proteins in the human brain. J Neurosci Res 93(7):987\u2013998","journal-title":"J Neurosci Res"},{"key":"9860_CR60","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.neuint.2017.10.014","volume":"112","author":"J Hull","year":"2018","unstructured":"Hull J, Usmari Moraes M, Brookes E, Love S, Conway ME (2018) Distribution of the branched-chain \u03b1-ketoacid dehydrogenase complex E1\u03b1 subunit and glutamate dehydrogenase in the human brain and their role in neuro-metabolism. Neurochem Int 112:49\u201358","journal-title":"Neurochem Int"},{"issue":"12","key":"9860_CR61","doi-asserted-by":"publisher","first-page":"1475","DOI":"10.1093\/jn\/118.12.1475","volume":"118","author":"SM Hutson","year":"1988","unstructured":"Hutson SM (1988) Subcellular distribution of branched-chain aminotransferase activity in rat tissues. J Nutr 118(12):1475\u20131481","journal-title":"J Nutr"},{"issue":"2","key":"9860_CR62","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1093\/ajcn\/34.2.173","volume":"34","author":"SM Hutson","year":"1981","unstructured":"Hutson SM, Harper AE (1981) Blood and tissue branched-chain amino and alpha-keto acid concentrations: effect of diet, starvation, and disease. Am J Clin Nutr 34(2):173\u2013183","journal-title":"Am J Clin Nutr"},{"issue":"22","key":"9860_CR63","doi-asserted-by":"crossref","first-page":"8126","DOI":"10.1016\/S0021-9258(17)34371-5","volume":"253","author":"SM Hutson","year":"1978","unstructured":"Hutson SM, Cree TC, Harper AE (1978) Regulation of leucine and alpha-ketoisocaproate metabolism in skeletal muscle. J Biol Chem 253(22):8126\u20138133","journal-title":"J Biol Chem"},{"issue":"2","key":"9860_CR64","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1046\/j.1471-4159.1998.71020863.x","volume":"71","author":"SM Hutson","year":"1998","unstructured":"Hutson SM, Berkich D, Drown P, Xu B, Aschner M, LaNoue KF (1998) Role of branched-chain aminotransferase isoenzymes and gabapentin in neurotransmitter metabolism. J Neurochem 71(2):863\u2013874","journal-title":"J Neurochem"},{"issue":"3","key":"9860_CR65","doi-asserted-by":"publisher","first-page":"846S","DOI":"10.1093\/jn\/131.3.846S","volume":"131","author":"SM Hutson","year":"2001","unstructured":"Hutson SM, Lieth E, LaNoue KF (2001) Function of leucine in excitatory neurotransmitter metabolism in the central nervous system. J Nutr 131(3):846S\u2013850S","journal-title":"J Nutr"},{"issue":"4","key":"9860_CR66","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1016\/j.neuint.2011.05.001","volume":"59","author":"SM Hutson","year":"2011","unstructured":"Hutson SM, Islam MM, Zaganas I (2011) Interaction between glutamate dehydrogenase (GDH) and L-leucine catabolic enzymes: intersecting metabolic pathways. Neurochem Int 59(4):518\u2013524","journal-title":"Neurochem Int"},{"issue":"5","key":"9860_CR67","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1016\/j.neuint.2004.03.007","volume":"45","author":"MR Hynd","year":"2004","unstructured":"Hynd MR, Scott HL, Dodd PR (2004) Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease. Neurochem Int 45(5):583\u2013595","journal-title":"Neurochem Int"},{"key":"9860_CR68","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1093\/oxfordjournals.jbchem.a128277","volume":"59","author":"A Ichihara","year":"1966","unstructured":"Ichihara A, Koyama E (1966) Transaminase of branched chain amino acids. J Biochem 59:160\u2013169","journal-title":"J Biochem"},{"issue":"16","key":"9860_CR69","doi-asserted-by":"publisher","first-page":"11893","DOI":"10.1074\/jbc.M700198200","volume":"282","author":"MM Islam","year":"2007","unstructured":"Islam MM, Wallin R, Wynn RM, Conway M, Fujii H, Mobley JA, Chuang DT, Hutson SM (2007) A novel branched-chain amino acid metabolon. Protein-protein interactions in a supramolecular complex. J Biol Chem 282(16):11893\u201311903","journal-title":"J Biol Chem"},{"issue":"1","key":"9860_CR70","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1074\/jbc.M109.048777","volume":"285","author":"MM Islam","year":"2010","unstructured":"Islam MM, Nautiyal M, Wynn RM et al (2010) Branched-chain amino acid metabolon: interaction of glutamate dehydrogenase with the mitochondrial branched-chain aminotransferase (BCATm). J Biol Chem 285(1):265\u2013276","journal-title":"J Biol Chem"},{"issue":"1","key":"9860_CR71","doi-asserted-by":"publisher","first-page":"97","DOI":"10.3233\/JAD-2007-11113","volume":"11","author":"CP Jacob","year":"2007","unstructured":"Jacob CP, Koutsilieri E, Bartl J, Neuen-Jacob E, Arzberger T, Zander N, Ravid R, Roggendorf W, Riederer P, Gr\u00fcnblatt E (2007) Alterations in expression of glutamatergic transporters and receptors in sporadic Alzheimer's disease. J Alzheimers Dis 11(1):97\u2013116","journal-title":"J Alzheimers Dis"},{"issue":"6","key":"9860_CR72","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1007\/s00234-003-0955-7","volume":"45","author":"W Jan","year":"2003","unstructured":"Jan W, Zimmerman RA, Wang ZJ, Berry GT, Kaplan PB, Kaye EM (2003) MR diffusion imaging and MR spectroscopy of maple syrup urine disease during acute metabolic decompensation. Neuroradiology 45(6):393\u2013399","journal-title":"Neuroradiology"},{"issue":"8","key":"9860_CR73","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1089\/neu.2012.2491","volume":"30","author":"CB Jeter","year":"2013","unstructured":"Jeter CB, Hergenroeder GW, Ward III NH, Moore AN, Dash PK (2013) Human mild traumatic brain injury decreases circulating branched-chain amino acids and their metabolite levels. J Neurotrauma 30(8):671\u2013679","journal-title":"J Neurotrauma"},{"issue":"5","key":"9860_CR74","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1016\/j.neurobiolaging.2004.07.001","volume":"26","author":"LG Kaiser","year":"2005","unstructured":"Kaiser LG, Schuff N, Cashdollar N, Weiner MW (2005) Age-related glutamate and glutamine concentration changes in normal human brain: 1H MR spectroscopy study at 4 T. Neurobiol Aging 26(5):665\u2013672","journal-title":"Neurobiol Aging"},{"key":"9860_CR75","doi-asserted-by":"publisher","first-page":"482","DOI":"10.3389\/fneur.2019.00482","volume":"10","author":"S Kalra","year":"2019","unstructured":"Kalra S (2019) Magnetic resonance spectroscopy in ALS. Front Neurol 10:482","journal-title":"Front Neurol"},{"issue":"3","key":"9860_CR76","doi-asserted-by":"publisher","first-page":"1304","DOI":"10.1046\/j.1471-4159.1998.70031304.x","volume":"70","author":"K Kanamori","year":"1998","unstructured":"Kanamori K, Ross BD, Kondrat RW (1998) Rate of glutamate synthesis from leucine in rat brain measured in vivo by 15N NMR. J Neurochem 70(3):1304\u20131315","journal-title":"J Neurochem"},{"issue":"Spec No 2","key":"9860_CR77","doi-asserted-by":"publisher","first-page":"S146","DOI":"10.1259\/bjr\/60346217","volume":"80","author":"K Kantarci","year":"2007","unstructured":"Kantarci K (2007) Magnetic resonance spectroscopy in dementia. Br J Radiol. 80(Spec No 2):S146\u2013S152","journal-title":"Br J Radiol."},{"key":"9860_CR137","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/j.neurobiolaging.2017.04.024","volume":"56","author":"K Kantarci","year":"2017","unstructured":"Kantarci K, Murray ME, Schwarz CG, Reid RI, Przybelski SA, Lesnick T, Zuk SM, Raman MR, Senjem ML, Gunter JL, Boeve BF, Knopman DS, Parisi JE, Petersen RC, Jack CR Jr, Dickson DW (2017) White-matter integrity on DTI and the pathologic staging of Alzheimer's disease. Neurobiol Aging 56:172\u2013179. https:\/\/doi.org\/10.1016\/j.neurobiolaging.2017.04.024","journal-title":"Neurobiol Aging"},{"key":"9860_CR78","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/S0169-328X(99)00318-6","volume":"75","author":"N Kholodilov","year":"2000","unstructured":"Kholodilov N, Neystat M, Oo T, Hutson S, Burke R (2000) Upregulation of cytosolic branched chain aminotransferase in substantia nigra following developmental striatal target injury. Mol Brain Res 75:281\u2013286","journal-title":"Mol Brain Res"},{"key":"9860_CR79","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.neuroscience.2017.02.011","volume":"348","author":"JG Kilian","year":"2017","unstructured":"Kilian JG, Hsu HW, Mata K, Wolf FW, Kitazawa M (2017) Astrocyte transport of glutamate and neuronal activity reciprocally modulate tau pathology in Drosophila. Neuroscience 348:191\u2013200","journal-title":"Neuroscience"},{"issue":"2","key":"9860_CR80","doi-asserted-by":"publisher","first-page":"401","DOI":"10.3233\/JAD-170424","volume":"60","author":"T Kishi","year":"2017","unstructured":"Kishi T, Matsunaga S, Oya K, Nomura I, Ikuta T, Iwata N (2017) Memantine for Alzheimer's Disease: an updated systematic review and meta-analysis. J Alzheimers Dis 60(2):401\u2013425","journal-title":"J Alzheimers Dis"},{"issue":"5","key":"9860_CR81","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1002\/jimd.12135","volume":"42","author":"I Knerr","year":"2019","unstructured":"Knerr I, Colombo R, Urquhart J, Morais A, Merinero B, Oyarzabal A, P\u00e9rez B, Jones SA, Perveen R, Preece MA, Rogers Y, Treacy EP, Mayne P, Zampino G, MacKinnon S, Wassmer E, Yue WW, Robinson I, Rodr\u00edguez-Pombo P, Olpin SE, Banka S (2019) Expanding the genetic and phenotypic spectrum of branched-chain amino acid transferase 2 deficiency. J Inherit Metab Dis 42(5):809\u2013817","journal-title":"J Inherit Metab Dis"},{"issue":"1\u20132","key":"9860_CR138","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/0006-8993(91)91140-V","volume":"548","author":"JY Koh","year":"1991","unstructured":"Koh JY, Choi DW (1991) Selective blockade of non-NMDA receptors does not block rapidly triggered glutamate-induced neuronal death. Brain Res 548(1\u20132):318\u2013321","journal-title":"Brain Res"},{"issue":"1","key":"9860_CR82","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1111\/ene.13439","volume":"25","author":"CA Lane","year":"2018","unstructured":"Lane CA, Hardy J, Schott JM (2018) Alzheimer's disease. Eur J Neurol 25(1):59\u201370","journal-title":"Eur J Neurol"},{"issue":"5","key":"9860_CR83","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1002\/jnr.10064","volume":"66","author":"KF LaNoue","year":"2001","unstructured":"LaNoue KF, Berkich DA, Conway M, Barber AJ, Hu LY, Taylor C, Hutson S (2001) Role of specific aminotransferases in de novo glutamate synthesis and redox shuttling in the retina. J Neurosci Res 66(5):914\u2013922","journal-title":"J Neurosci Res"},{"key":"9860_CR84","doi-asserted-by":"publisher","first-page":"1875","DOI":"10.1111\/j.1471-4159.1990.tb05771.x","volume":"55","author":"JW Lazarewicz","year":"1990","unstructured":"Lazarewicz JW, Wroblewski JT, Costa E (1990) N-Methyld-aspartate-sensitive glutamate receptors induce calcium-mediated arachidonic acid release in primary cultures of cerebellar granule cells. J Neurochem 55:1875\u20131881","journal-title":"J Neurochem"},{"issue":"6","key":"9860_CR85","doi-asserted-by":"publisher","first-page":"1712","DOI":"10.1046\/j.1471-4159.2001.00156.x","volume":"76","author":"E Lieth","year":"2001","unstructured":"Lieth E, LaNoue KF, Berkich DA, Xu B, Ratz M, Taylor C, Hutson SM (2001) Nitrogen shuttling between neurons and glial cells during glutamate synthesis. J Neurochem 76(6):1712\u20131723","journal-title":"J Neurochem"},{"issue":"51","key":"9860_CR86","doi-asserted-by":"publisher","first-page":"48196","DOI":"10.1074\/jbc.M104320200","volume":"276","author":"HM Lin","year":"2001","unstructured":"Lin HM, Kaneshige M, Zhao L, Zhang X, Hanover JA, Cheng SY (2001) An isoform of branched-chain aminotransferase is a novel co-repressor for thyroid hormone nuclear receptors. J Biol Chem 276(51):48196\u201348205","journal-title":"J Biol Chem"},{"key":"9860_CR87","doi-asserted-by":"publisher","first-page":"43","DOI":"10.3389\/fnins.2019.00043","volume":"13","author":"J Liu","year":"2019","unstructured":"Liu J, Chang L, Song Y, Li H, Wu Y (2019) The role of NMDA receptors in Alzheimer's disease. Front Neurosci 13:43","journal-title":"Front Neurosci"},{"issue":"5","key":"9860_CR88","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1016\/j.jalz.2013.08.282","volume":"10","author":"AC Londono","year":"2014","unstructured":"Londono AC, Castellanos FX, Arbelaez A, Ruiz A, Aguirre-Acevedo DC, Richardson AM, Easteal S, Lidbury BA, Arcos-Burgos M, Lopera F (2014) An 1H-MRS framework predicts the onset of Alzheimer's disease symptoms in PSEN1 mutation carriers. Alzheimers Dement 10(5):552\u2013561","journal-title":"Alzheimers Dement"},{"issue":"13","key":"9860_CR89","doi-asserted-by":"publisher","first-page":"2045","DOI":"10.1097\/00001756-200409150-00010","volume":"15","author":"F Madeddu","year":"2004","unstructured":"Madeddu F, Naska S, Bozzi Y (2004) BDNF down-regulates the caspase 3 pathway in injured geniculo-cortical neurones. NeuroReport 15(13):2045\u20132049","journal-title":"NeuroReport"},{"issue":"4","key":"9860_CR90","doi-asserted-by":"publisher","first-page":"e0123289","DOI":"10.1371\/journal.pone.0123289","volume":"10","author":"S Matsunaga","year":"2015","unstructured":"Matsunaga S, Kishi T, Iwata N (2015) Memantine monotherapy for Alzheimer's disease: a systematic review and meta-analysis. PLoS ONE 10(4):e0123289","journal-title":"PLoS ONE"},{"issue":"1","key":"9860_CR91","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/0006-8993(92)90323-2","volume":"582","author":"MP Mattson","year":"1992","unstructured":"Mattson MP (1992) Effects of microtubule stabilization and destabilization on tau immunoreactivity in cultured hippocampal neurons. Brain Res 582(1):107\u2013118","journal-title":"Brain Res"},{"issue":"4\u20135","key":"9860_CR92","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1016\/S0143-4160(03)00128-3","volume":"34","author":"MP Mattson","year":"2003","unstructured":"Mattson MP, Chan SL (2003) Neuronal and glial calcium signaling in Alzheimer's disease. Cell Calcium 34(4\u20135):385\u2013397","journal-title":"Cell Calcium"},{"issue":"2","key":"9860_CR93","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1542\/peds.23.2.348","volume":"23","author":"JH Menkes","year":"1959","unstructured":"Menkes JH (1959) Maple syrup disease; isolation and identification of organic acids in the urine. Pediatrics 23(2):348\u2013353","journal-title":"Pediatrics"},{"key":"9860_CR94","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1176\/appi.ajp.162.4.667","volume":"162","author":"PJ Modrego","year":"2005","unstructured":"Modrego PJ, Fayed N, Pina MA (2005) Conversion from mild cognitive impairment to probable Alzheimer\u2019s disease predicted by brain magnetic resonance spectroscopy. Am J Psychiatry 162:667\u2013675","journal-title":"Am J Psychiatry"},{"key":"9860_CR95","doi-asserted-by":"publisher","DOI":"10.1093\/biohorizons\/hzy001\/4969341","author":"MU Moraes","year":"2018","unstructured":"Moraes MU, Gaudet T (2018) Immunotherapeutic and pharmacological approaches for the treatment of Alzheimer\u2019s disease. Biosci Horiz. https:\/\/doi.org\/10.1093\/biohorizons\/hzy001\/4969341","journal-title":"Biosci Horiz"},{"key":"9860_CR96","doi-asserted-by":"publisher","first-page":"187297","DOI":"10.1155\/2012\/187297","volume":"2012","author":"M Nizzari","year":"2012","unstructured":"Nizzari M, Thellung S, Corsaro A, Villa V, Pagano A, Porcile C, Russo C, Florio T (2012) Neurodegeneration in Alzheimer disease: role of amyloid precursor protein and presenilin 1 intracellular signaling. J Toxicol 2012:187297","journal-title":"J Toxicol"},{"key":"9860_CR97","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1146\/annurev-neuro-061010-113613","volume":"34","author":"RJ O'Brien","year":"2011","unstructured":"O'Brien RJ, Wong PC (2011) Amyloid precursor protein processing and Alzheimer's disease. Annu Rev Neurosci 34:185\u2013204","journal-title":"Annu Rev Neurosci"},{"issue":"45","key":"9860_CR98","doi-asserted-by":"publisher","first-page":"31891","DOI":"10.1074\/jbc.274.45.31891","volume":"274","author":"RL O'Kane","year":"1999","unstructured":"O'Kane RL, Mart\u00ednez-L\u00f3pez I, DeJoseph MR, Vi\u00f1a JR, Hawkins RA (1999) Na(+)-dependentglutamate transporters (EAAT1, EAAT2, and EAAT3) of the blood-brain barrier. A mechanism for glutamate removal. J Biol Chem 274(45):31891\u201331895","journal-title":"J Biol Chem"},{"issue":"4","key":"9860_CR99","doi-asserted-by":"publisher","first-page":"E622","DOI":"10.1152\/ajpendo.00187.2004","volume":"287","author":"RL O'Kane","year":"2004","unstructured":"O'Kane RL, Vi\u00f1a JR, Simpson I, Hawkins RA (2004) Na+ -dependent neutral amino acid transporters A, ASC, and N of the blood-brain barrier: mechanisms for neutral amino acid removal. American J Phys Endocrin Met 287(4):E622\u2013E629","journal-title":"American J Phys Endocrin Met"},{"issue":"5","key":"9860_CR100","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1002\/ana.410010502","volume":"1","author":"WH Oldendorf","year":"1977","unstructured":"Oldendorf WH, Cornford ME, Brown WJ (1977) The large apparent work capability of the blood-brain barrier: a study of the mitochondrial content of capillary endothelial cells in brain and other tissues of the rat. Ann Neurol 1(5):409\u2013417","journal-title":"Ann Neurol"},{"issue":"50","key":"9860_CR101","doi-asserted-by":"publisher","first-page":"11273","DOI":"10.1523\/JNEUROSCI.3564-04.2004","volume":"24","author":"G Oz","year":"2004","unstructured":"Oz G, Berkich DA, Henry PG, Xu Y, LaNoue K, Hutson SM, Gruetter R (2004) Neuroglial metabolism in the awake rat brain: CO2 fixation increases with brain activity. J Neurosci 24(50):11273\u201311279","journal-title":"J Neurosci"},{"issue":"2","key":"9860_CR102","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.molmed.2007.12.002","volume":"14","author":"PH Reddy","year":"2008","unstructured":"Reddy PH, Beal MF (2008) Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. Trends Mol Med 14(2):45\u201353","journal-title":"Trends Mol Med"},{"key":"9860_CR103","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1038\/nrneurol.2011.2","volume":"7","author":"C Reitz","year":"2011","unstructured":"Reitz C, Brayne C, Mayeux R (2011) Epidemiology of Alzheimer disease. Nat Rev Neurol 7:137\u2013152","journal-title":"Nat Rev Neurol"},{"issue":"1","key":"9860_CR104","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.neurobiolaging.2014.07.030","volume":"36","author":"F Riese","year":"2015","unstructured":"Riese F, Gietl A, Z\u00f6lch N, Henning A, O'Gorman R, K\u00e4lin AM, Leh SE, Buck A, Warnock G, Edden RA, Luechinger R, Hock C, Kollias S, Michels L (2015) Posterior cingulate \u03b3-aminobutyric acid and glutamate\/glutamine are reduced in amnestic mild cognitive impairment and are unrelated to amyloid deposition and apolipoprotein E genotype. Neurobiol Aging 36(1):53\u201359","journal-title":"Neurobiol Aging"},{"key":"9860_CR105","doi-asserted-by":"publisher","first-page":"1483","DOI":"10.1523\/JNEUROSCI.05-06-01483.1985","volume":"5","author":"SM Rothman","year":"1985","unstructured":"Rothman SM (1985) The neurotoxicity of excitatory amino acids is produced by passive chloride influx. J Neurosci 5:1483\u20131489","journal-title":"J Neurosci"},{"issue":"5","key":"9860_CR106","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1016\/j.neurobiolaging.2009.05.002","volume":"32","author":"R Rupsingh","year":"2011","unstructured":"Rupsingh R, Borrie M, Smith M, Wells JL, Bartha R (2011) Reduced hippocampal glutamate in Alzheimer disease. Neurobiol Aging 32(5):802\u2013810","journal-title":"Neurobiol Aging"},{"issue":"1","key":"9860_CR107","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/s001090000077","volume":"78","author":"R Sattler","year":"2000","unstructured":"Sattler R, Tymianski M (2000) Molecular mechanisms of calcium-dependent excitotoxicity. J Mol Med 78(1):3\u201313","journal-title":"J Mol Med"},{"issue":"4","key":"9860_CR108","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1007\/s00213-004-2105-2","volume":"179","author":"A Scarn\u00e0","year":"2005","unstructured":"Scarn\u00e0 A, McTavish SF, Cowen PJ, Goodwin GM, Rogers RD (2005) The effects of a branched chain amino acid mixture supplemented with tryptophan on biochemical indices of neurotransmitter function and decision-making. Psychopharmacology 179(4):761\u2013768","journal-title":"Psychopharmacology"},{"issue":"1","key":"9860_CR109","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.ymgme.2004.01.016","volume":"82","author":"S Sch\u00f6nberger","year":"2004","unstructured":"Sch\u00f6nberger S, Schweiger B, Schwahn B, Schwarz M, Wendel U (2004) Dysmyelination in the brain of adolescents and young adults with maple syrup urine disease. Mol Genet Metab 82(1):69\u201375","journal-title":"Mol Genet Metab"},{"issue":"3","key":"9860_CR110","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1016\/j.bbadis.2003.09.010","volume":"1639","author":"AM Sgaravatti","year":"2003","unstructured":"Sgaravatti AM, Rosa RB, Schuck PF, Ribeiro CA, Wannmacher CM, Wyse AT, Dutra-Filho CS, Wajner M (2003) Inhibition of brain energy metabolism by the alpha-keto acids accumulating in maple syrup urine disease. Biochim Biophys Acta 1639(3):232\u2013238","journal-title":"Biochim Biophys Acta"},{"issue":"1\u20132","key":"9860_CR111","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1016\/0006-8993(85)90552-9","volume":"329","author":"RP Shank","year":"1985","unstructured":"Shank RP, Bennett GS, Freytag SO, Campbell GL (1985) Pyruvate carboxylase: an astrocyte-specific enzyme implicated in the replenishment of amino acid neurotransmitter pools. Brain Res 329(1\u20132):364\u2013367","journal-title":"Brain Res"},{"key":"9860_CR112","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/0896-6273(88)90076-1","volume":"1","author":"R Siman","year":"1988","unstructured":"Siman R, Noszek JC (1988) Excitatory amino acids activate calpain I and induce structural protein breakdown in vivo. Neuron 1:279\u2013287","journal-title":"Neuron"},{"issue":"5","key":"9860_CR113","doi-asserted-by":"publisher","first-page":"1651","DOI":"10.1111\/j.1471-4159.1987.tb01039.x","volume":"49","author":"QR Smith","year":"1987","unstructured":"Smith QR, Momma S, Aoyagi M, Rapoport SI (1987) Kinetics of neutral amino acid transport across the blood-brain barrier. J Neurochem 49(5):1651\u20131658","journal-title":"J Neurochem"},{"issue":"3","key":"9860_CR114","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.1111\/j.1471-4159.1993.tb03641.x","volume":"61","author":"U Sonnewald","year":"1993","unstructured":"Sonnewald U, Westergaard N, Petersen SB, Unsg\u00e5rd G, Schousboe A (1993) Metabolism of [U-13C] glutamate in astrocytes studied by 13C NMR spectroscopy: incorporation of more label into lactate than into glutamine demonstrates the importance of the tricarboxylic acid cycle. J Neurochem 61(3):1179\u20131182","journal-title":"J Neurochem"},{"issue":"8","key":"9860_CR115","doi-asserted-by":"publisher","first-page":"e877","DOI":"10.1038\/tp.2016.140","volume":"6","author":"L Su","year":"2016","unstructured":"Su L, Blamire AM, Watson R, He J, Hayes L, O'Brien JT (2016) Whole-brain patterns of (1)H-magnetic resonance spectroscopy imaging in Alzheimer's disease and dementia with Lewy bodies. Transl Psychiatry 6(8):e877","journal-title":"Transl Psychiatry"},{"issue":"3","key":"9860_CR116","doi-asserted-by":"publisher","first-page":"797","DOI":"10.3233\/JAD-190114","volume":"71","author":"T Supasitthumrong","year":"2019","unstructured":"Supasitthumrong T, Tunvirachaisakul C, Aniwattanapong D, Tangwongchai S, Chuchuen P, Tawankanjanachot I, Snabboon T, Hemrungrojn S, Carvalho AF, Maes M (2019) peripheral blood biomarkers coupled with the apolipoprotein e4 genotype are strongly associated with semantic and episodic memory impairments in elderly subjects with amnestic mild cognitive impairment and Alzheimer's disease. J Alzheimers Dis 71(3):797\u2013811","journal-title":"J Alzheimers Dis"},{"issue":"1","key":"9860_CR117","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1093\/ajcn\/68.1.72","volume":"68","author":"A Suryawan","year":"1998","unstructured":"Suryawan A, Hawes JW, Harris RA et al (1998) A molecular model of human branched-chain amino acid metabolism. Am J Clin Nutr 68(1):72\u201381","journal-title":"Am J Clin Nutr"},{"issue":"4","key":"9860_CR118","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1002\/cne.20200","volume":"477","author":"AJ Sweatt","year":"2004","unstructured":"Sweatt AJ, Garcia-Espinosa MA, Wallin R et al (2004a) Branched-chain amino acids and neurotransmitter metabolism: expression of cytosolic branched-chain aminotransferase (BCATc) in the cerebellum and hippocampus. J Comp Neuro 477(4):360\u2013370","journal-title":"J Comp Neuro"},{"issue":"1","key":"9860_CR119","doi-asserted-by":"publisher","first-page":"E64","DOI":"10.1152\/ajpendo.00276.2003","volume":"286","author":"AJ Sweatt","year":"2004","unstructured":"Sweatt AJ, Wood M, Suryawan A, Wallin R, Willingham MC, Hutson SM (2004b) Branched-chain amino acid catabolism: unique segregation of pathway enzymes in organ systems and peripheral nerves. Am J Physiol Endocrinol Metab 286(1):E64\u201376","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"1","key":"9860_CR120","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1016\/j.neuroscience.2008.02.075","volume":"158","author":"VI Teichberg","year":"2009","unstructured":"Teichberg VI, Cohen-Kashi-Malina K, Cooper I, Zlotnik A (2009) Homeostasis of glutamate in brain fluids: an accelerated brain-to-blood efflux of excess glutamate is produced by blood glutamate scavenging and offers protection from neuropathologies. Neuroscience 158(1):301\u2013308","journal-title":"Neuroscience"},{"issue":"4","key":"9860_CR121","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1016\/j.nrl.2015.08.002","volume":"33","author":"P Tellechea","year":"2018","unstructured":"Tellechea P, Pujol N, Esteve-Belloch P, Echeveste B, Garc\u00eda-Eulate MR, Arbizu J, Riverol M (2018) Early- and late-onset Alzheimer disease: are they the same entity? Neurologia 33(4):244\u2013253","journal-title":"Neurologia"},{"issue":"2\u20133","key":"9860_CR122","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1053\/plac.2000.0603","volume":"22","author":"NG Than","year":"2001","unstructured":"Than NG, S\u00fcmegi B, Than GN, Bellyei S, Bohn H (2001) Molecular cloning and characterization of placental tissue protein 18 (PP18a)\/human mitochondrial branched-chain aminotransferase (BCATm) and its novel alternatively spliced PP18b variant. Placenta 22(2\u20133):235\u2013243","journal-title":"Placenta"},{"key":"9860_CR123","doi-asserted-by":"publisher","first-page":"5541","DOI":"10.2147\/IJN.S200490","volume":"14","author":"S Tiwari","year":"2019","unstructured":"Tiwari S, Atluri V, Kaushik A, Yndart A, Nair M (2019) Alzheimer's disease: pathogenesis, diagnostics, and therapeutics. Int J Nanomedicine 14:5541\u20135554","journal-title":"Int J Nanomedicine"},{"key":"9860_CR124","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2019.09.075","author":"M Tolar","year":"2019","unstructured":"Tolar M, Abushakra S, Sabbagh M (2019) The path forward in Alzheimer's disease therapeutics: reevaluating the amyloid cascade hypothesis. Alzheimers Dement. https:\/\/doi.org\/10.1016\/j.jalz.2019.09.075","journal-title":"Alzheimers Dement"},{"issue":"2","key":"9860_CR125","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1111\/j.1471-4159.2011.07208.x","volume":"117","author":"Y Uchida","year":"2011","unstructured":"Uchida Y, Ohtsuki S, Katsukura Y, Ikeda C, Suzuki T, Kamiie J, Terasaki T (2011) Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors. J Neurochem 117(2):333\u2013345","journal-title":"J Neurochem"},{"issue":"3","key":"9860_CR126","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1007\/s00726-011-1202-x","volume":"43","author":"RN Vuille-Dit-Bille","year":"2012","unstructured":"Vuille-Dit-Bille RN, Ha-Huy R, Stover JF (2012) Changes in plasma phenylalanine, isoleucine, leucine, and valine are associated with significant changes in intracranial pressure and jugular venous oxygen saturation in patients with severe traumatic brain injury. Amino Acids 43(3):1287\u20131296","journal-title":"Amino Acids"},{"issue":"5","key":"9860_CR127","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1007\/s10545-015-9814-z","volume":"38","author":"XL Wang","year":"2015","unstructured":"Wang XL, Li CJ, Xing Y, Yang YH, Jia JP (2015a) Hypervalinemia and hyperleucine-isoleucinemia caused by mutations in the branched-chain-amino-acid aminotransferase gene. J Inherit Metab Dis 38(5):855\u2013861","journal-title":"J Inherit Metab Dis"},{"issue":"4","key":"9860_CR128","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.3233\/JAD-143225","volume":"46","author":"H Wang","year":"2015","unstructured":"Wang H, Tan L, Wang HF, Liu Y, Yin RH, Wang WY, Chang XL, Jiang T, Yu JT (2015b) Magnetic resonance spectroscopy in Alzheimer's disease: systematic review and meta-analysis. J Alzheimers Dis 46(4):1049\u20131070","journal-title":"J Alzheimers Dis"},{"issue":"1","key":"9860_CR129","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1186\/s13195-017-0294-2","volume":"9","author":"C Wattmo","year":"2017","unstructured":"Wattmo C, Wallin \u00c5K (2017) Early\u2014versus late-onset Alzheimer's disease in clinical practice: cognitive and global outcomes over 3 years. Alzheimers Res Ther 9(1):70","journal-title":"Alzheimers Res Ther"},{"issue":"1","key":"9860_CR130","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1002\/(SICI)1098-1136(199709)21:1<92::AID-GLIA10>3.0.CO;2-W","volume":"21","author":"M Yudkoff","year":"1997","unstructured":"Yudkoff M (1997) Brain metabolism of branched-chain amino acids. Glia 21(1):92\u201398","journal-title":"Glia"},{"issue":"1","key":"9860_CR131","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1007\/s11064-016-2057-z","volume":"42","author":"M Yudkoff","year":"2017","unstructured":"Yudkoff M (2017) Interactions in the metabolism of glutamate and the branched-chain amino acids and ketoacids in the CNS. Neurochem Res. 42(1):10\u201318","journal-title":"Neurochem Res."},{"issue":"1","key":"9860_CR132","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/0006-291X(83)90985-3","volume":"115","author":"M Yudkoff","year":"1983","unstructured":"Yudkoff M, Nissim I, Kim S, Pleasure D, Hummeler K, Segal S (1983) [15N] leucine as a source of [15N] glutamate in organotypic cerebellar explants. Biochem Biophys Res Commun 115(1):174\u2013179","journal-title":"Biochem Biophys Res Commun"},{"issue":"5","key":"9860_CR133","doi-asserted-by":"publisher","first-page":"2136","DOI":"10.1046\/j.1471-4159.1996.66052136.x","volume":"66","author":"M Yudkoff","year":"1996","unstructured":"Yudkoff M, Daikhin Y, Nelson D, Nissim I, Ereci\u0144ska M (1996) Neuronal metabolism of branched-chain amino acids: flux through the aminotransferase pathway in synaptosomes. J Neurochem 66(5):2136\u20132145","journal-title":"J Neurochem"},{"issue":"6","key":"9860_CR134","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.1007\/s11064-007-9548-x","volume":"33","author":"A Zlotnik","year":"2008","unstructured":"Zlotnik A, Gurevich B, Cherniavsky E, Tkachov S, Matuzani-Ruban A, Leon A, Shapira Y, Teichberg VI (2008) The contribution of the blood glutamate scavenging activity of pyruvate to its neuroprotective properties in a rat model of closed head injury. Neurochem Res 33(6):1044\u20131050","journal-title":"Neurochem Res"},{"issue":"1","key":"9860_CR135","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1097\/ALN.0b013e31823d7731","volume":"116","author":"A Zlotnik","year":"2012","unstructured":"Zlotnik A, Sinelnikov I, Gruenbaum BF, Gruenbaum SE, Dubilet M, Dubilet E, Leibowitz A, Ohayon S, Regev A, Boyko M, Shapira Y, Teichberg VI (2012) Effect of glutamate and blood glutamate scavengers oxaloacetate and pyruvate on neurological outcome and pathohistology of the hippocampus after traumatic brain injury in rats. Anesthesiology 116(1):73\u201383","journal-title":"Anesthesiology"}],"container-title":["Biogerontology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s10522-020-09860-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s10522-020-09860-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s10522-020-09860-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T13:00:42Z","timestamp":1722430842000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s10522-020-09860-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,11]]},"references-count":139,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2020,6]]}},"alternative-id":["9860"],"URL":"https:\/\/doi.org\/10.1007\/s10522-020-09860-4","relation":{},"ISSN":["1389-5729","1573-6768"],"issn-type":[{"value":"1389-5729","type":"print"},{"value":"1573-6768","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,11]]},"assertion":[{"value":"18 November 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 January 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 February 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}]}}