Abstract
Altered glutamatergic neurotransmission is thought to play a crucial role in the progression of Alzheimer’s disease (AD). Accordingly, the identification of peculiar biochemical patterns reflecting AD-related synaptopathy in blood and cerebrospinal fluid (CSF) could have relevant diagnostic and prognostic implications. In this study, we measured by High-Performance Liquid Chromatography the amount of glutamate, glutamine and glycine in post-mortem brain samples of AD patients, as well as in CSF and blood serum of drug-free subjects encompassing the whole AD clinical spectrum (pre-clinical AD, n = 18, mild cognitive impairment-AD, n = 29, dementia AD, n = 30). Interestingly, we found that glutamate and glycine levels, as well as total tau protein content, were significantly reduced in the superior frontal gyrus of patients with AD, compared with non-demented controls. No significant change was also found in glutamate, glutamine and glycine CSF concentrations between AD patients and neurological controls. Remarkably, serum glutamate levels were significantly higher in patients affected by early AD phases compared to controls, and were negatively correlated with CSF total tau levels. Conversely, serum glutamine concentration was significantly increased in AD patients, with a negative correlation with MMSE performances. Finally, we reported a significant correlation between serum l-glutamate concentrations and CDR score in female but not in male cohort of AD subjects. Overall, our results suggest that serum glutamate and glutamine levels in AD patients could vary across disease stages, potentially reflecting the progressive alteration of glutamatergic signaling during neurodegenerative processes.
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References
Adage T, Trillat AC, Quattropani A, Perrin D, Cavarec L, Shaw J, Guerassimenko O, Giachetti C, Greco B, Chumakov I, Halazy S, Roach A, Zaratin P (2008) In vitro and in vivo pharmacological profile of AS057278, a selective d-amino acid oxidase inhibitor with potential anti-psychotic properties. Eur Neuropsychopharmacol 18(3):200–214. https://doi.org/10.1016/j.euroneuro.2007.06.006
Bak LK, Schousboe A, Waagepetersen HS (2006) The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. J Neurochem 98(3):641–653. https://doi.org/10.1111/j.1471-4159.2006.03913.x
Biemans EA, Verhoeven-Duif NM, Gerrits J, Claassen JA, Kuiperij HB, Verbeek MM (2016) CSF d-serine concentrations are similar in Alzheimer’s disease, other dementias, and elderly controls. Neurobiol Aging 42:213–216. https://doi.org/10.1016/j.neurobiolaging.2016.03.017
Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82(4):239–259. https://doi.org/10.1007/BF00308809
Burbaeva G, Boksha IS, Tereshkina EB, Savushkina OK, Starodubtseva LI, Turishcheva MS (2005) Glutamate metabolizing enzymes in prefrontal cortex of Alzheimer’s disease patients. Neurochem Res 30(11):1443–1451. https://doi.org/10.1007/s11064-005-8654-x
Chen J, Herrup K (2012) Glutamine acts as a neuroprotectant against DNA damage, beta-amyloid and H2O2-induced stress. PLoS ONE 7(3):e33177. https://doi.org/10.1371/journal.pone.0033177
Chen KH, Reese EA, Kim H-W, Rapoport SI, Rao JS (2011) Disturbed neurotransmitter transporter expression in Alzheimer’s disease brain. J Alzheimers Dis 26(4):755–766. https://doi.org/10.3233/JAD-2011-110002
Chouraki V, Preis SR, Yang Q, Beiser A, Li S, Larson MG, Weinstein G, Wang TJ, Gerszten RE, Vasan RS, Seshadri S (2017) Association of amine biomarkers with incident dementia and Alzheimer’s disease in the Framingham Study. Alzheimers Dement 13(12):1327–1336. https://doi.org/10.1016/j.jalz.2017.04.009
Cui M, Jiang Y, Zhao Q, Zhu Z, Liang X, Zhang K, Wu W, Dong Q, An Y, Tang H, Ding D, Chen X (2020) Metabolomics and incident dementia in older Chinese adults: the Shanghai Aging Study. Alzheimer’s Dementia 16(5):779–788. https://doi.org/10.1002/alz.12074
D’Aniello A, Fisher G, Migliaccio N, Cammisa G, D’Aniello E, Spinelli P (2005) Amino acids and transaminases activity in ventricular CSF and in brain of normal and Alzheimer patients. Neurosci Lett 388(1):49–53. https://doi.org/10.1016/j.neulet.2005.06.030
De Rosa A, Mastrostefano F, Di Maio A, Nuzzo T, Saitoh Y, Katane M, Isidori AM, Caputo V, Marotta P, Falco G, De Stefano ME, Homma H, Usiello A, Errico F (2020) Prenatal expression of D-aspartate oxidase causes early cerebral D-aspartate depletion and influences brain morphology and cognitive functions at adulthood. Amino Acids. https://doi.org/10.1007/s00726-020-02839-y
Degrell I, Hellsing K, Nagy E, Niklasson F (1989) Amino acid concentrations in cerebrospinal fluid in presenile and senile dementia of Alzheimer type and multi-infarct dementia. Arch Gerontol Geriatr 9(2):123–135. https://doi.org/10.1016/0167-4943(89)90033-2
del Campo M, Mollenhauer B, Bertolotto A, Engelborghs S, Hampel H, Simonsen AH, Kapaki E, Kruse N, Le Bastard N, Lehmann S, Molinuevo JL, Parnetti L, Perret-Liaudet A, Saez-Valero J, Saka E, Urbani A, Vanmechelen E, Verbeek M, Visser PJ, Teunissen C (2012) Recommendations to standardize preanalytical confounding factors in Alzheimer’s and Parkinson’s disease cerebrospinal fluid biomarkers: an update. Biomark Med 6(4):419–430. https://doi.org/10.2217/bmm.12.46
Ellison DW, Beal MF, Mazurek MF, Bird ED, Martin JB (1986) A postmortem study of amino acid neurotransmitters in Alzheimer’s disease. Ann Neurol 20(5):616–621. https://doi.org/10.1002/ana.410200510
Gueli MC, Taibi G (2013) Alzheimer’s disease: amino acid levels and brain metabolic status. Neurol Sci 34(9):1575–1579. https://doi.org/10.1007/s10072-013-1289-9
Gunnersen D, Haley B (1992) Detection of glutamine synthetase in the cerebrospinal fluid of Alzheimer diseased patients: a potential diagnostic biochemical marker. Proc Natl Acad Sci U S A 89(24):11949–11953. https://doi.org/10.1073/pnas.89.24.11949
Hardingham GE, Bading H (2010) Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 11(10):682–696. https://doi.org/10.1038/nrn2911
Harkany T, Ábrahám I, Timmerman W, Laskay G, Tóth B, Sasvári M, Kónya C, Sebens JB, Korf J, Nyakas C, Zarándi M, Soós K, Penke B, Luiten PGM (2000) β-Amyloid neurotoxicity is mediated by a glutamate-triggered excitotoxic cascade in rat nucleus basalis. Eur J Neurosci 12(8):2735–2745. https://doi.org/10.1046/j.1460-9568.2000.00164.x
Hirtz D, Thurman DJ, Gwinn-Hardy K, Mohamed M, Chaudhuri AR, Zalutsky R (2007) How common are the “common” neurologic disorders? Neurology 68(5):326–337. https://doi.org/10.1212/01.wnl.0000252807.38124.a3
Huang D, Liu D, Yin J, Qian T, Shrestha S, Ni H (2016) Glutamate-glutamine and GABA in brain of normal aged and patients with cognitive impairment. Eur Radiol 27(7):2698–2705. https://doi.org/10.1007/s00330-016-4669-8
Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, Holtzman DM, Jagust W, Jessen F, Karlawish J, Liu E, Molinuevo JL, Montine T, Phelps C, Rankin KP, Rowe CC, Scheltens P, Siemers E, Snyder HM, Sperling R, Contributors (2018) NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement 14(4):535–562. https://doi.org/10.1016/j.jalz.2018.02.018
Jiménez-Jiménez FJ, Molina JA, Gómez P, Vargas C, de Bustos F, Benito-León J, Tallón-Barranco A, Ortí-Pareja M, Gasalla T, Arenas J (1998) Neurotransmitter amino acids in cerebrospinal fluid of patients with Alzheimer’s disease. J Neural Transmission 105(2–3):269–277. https://doi.org/10.1007/s007020050056
Jo S, Yarishkin O, Hwang YJ, Chun YE, Park M, Woo DH, Bae JY, Kim T, Lee J, Chun H, Park HJ, Lee DY, Hong J, Kim HY, Oh S-J, Park SJ, Lee H, Yoon B-E, Kim Y, Jeong Y, Shim I, Bae YC, Cho J, Kowall NW, Ryu H, Hwang E, Kim D, Lee CJ (2014) GABA from reactive astrocytes impairs memory in mouse models of Alzheimer’s disease. Nat Med 20(8):886–896. https://doi.org/10.1038/nm.3639
Johnson JW, Ascher P (1987) Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325(6104):529–531. https://doi.org/10.1038/325529a0
Kaiser E, Schoenknecht P, Kassner S, Hildebrandt W, Kinscherf R, Schroeder J (2010) Cerebrospinal fluid concentrations of functionally important amino acids and metabolic compounds in patients with mild cognitive impairment and Alzheimer’s disease. Neurodegenerative Diseases. https://doi.org/10.1159/000287953
Lauderback CM, Hackett JM, Huang FF, Keller JN, Szweda LI, Markesbery WR, Butterfield DA (2001) The glial glutamate transporter, GLT-1, is oxidatively modified by 4-hydroxy-2-nonenal in the Alzheimer’s disease brain: the role of Abeta1-42. J Neurochem 78(2):413–416. https://doi.org/10.1046/j.1471-4159.2001.00451.x
Lei M, Xu H, Li Z, Wang Z, O’Malley TT, Zhang D, Walsh DM, Xu P, Selkoe DJ, Li S (2016) Soluble Aβ oligomers impair hippocampal LTP by disrupting glutamatergic/GABAergic balance. Neurobiol Dis 85:111–121. https://doi.org/10.1016/j.nbd.2015.10.019
Lewerenz J, Maher P (2015) Chronic glutamate toxicity in neurodegenerative diseases-what is the evidence? Front Neurosci 9:469–469. https://doi.org/10.3389/fnins.2015.00469
Lin C-H, Yang H-T, Chiu C-C, Lane H-Y (2017) Blood levels of D-amino acid oxidase vs. D-amino acids in reflecting cognitive aging. Sci Rep 7(1):14849–14849. https://doi.org/10.1038/s41598-017-13951-7
Lowe SL, Bowen DM, Francis PT, Neary D (1990) Ante mortem cerebral amino acid concentrations indicate selective degeneration of glutamate-enriched neurons in Alzheimer’s disease. Neuroscience 38(3):571–577. https://doi.org/10.1016/0306-4522(90)90051-5
Madeira C, Lourenco MV, Vargas-Lopes C, Suemoto CK, Brandao CO, Reis T, Leite RE, Laks J, Jacob-Filho W, Pasqualucci CA, Grinberg LT, Ferreira ST, Panizzutti R (2015) d-serine levels in Alzheimer’s disease: implications for novel biomarker development. Transl Psychiatry 5:e561. https://doi.org/10.1038/tp.2015.52
Madeira C, Vargas-Lopes C, Brandão CO, Reis T, Laks J, Panizzutti R, Ferreira ST (2018) Elevated glutamate and glutamine levels in the cerebrospinal fluid of patients with probable Alzheimer’s disease and depression. Front Psychiatry 9:561–561. https://doi.org/10.3389/fpsyt.2018.00561
Manyevitch R, Protas M, Scarpiello S, Deliso M, Bass B, Nanajian A, Chang M, Thompson SM, Khoury N, Gonnella R, Trotz M, Moore DB, Harms E, Perry G, Clunes L, Ortiz A, Friedrich JO, Murray IVJ (2018) Evaluation of metabolic and synaptic dysfunction hypotheses of Alzheimer’s disease (AD): a meta-analysis of CSF markers. Curr Alzheimer Res 15(2):164–181. https://doi.org/10.2174/1567205014666170921122458
Martinez M, Frank A, Diez-Tejedor E, Hernanz A (1993) Amino acid concentrations in cerebrospinal fluid and serum in Alzheimer’s disease and vascular dementia. J Neural Transmission Parkinson’s Dis Dementia Section 6(1):1–9. https://doi.org/10.1007/bf02252617
Masliah E, Alford M, DeTeresa R, Mallory M, Hansen L (1996) Deficient glutamate transport is associated with neurodegeneration in Alzheimer’s disease. Ann Neurol 40(5):759–766. https://doi.org/10.1002/ana.410400512
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA work group under the auspices of department of health and human services task force on Alzheimer’s disease. Neurology 34(7):939–944. https://doi.org/10.1212/wnl.34.7.939
Nuzzo T, Sacchi S, Errico F, Keller S, Palumbo O, Florio E, Punzo D, Napolitano F, Copetti M, Carella M, Chiariotti L, Bertolino A, Pollegioni L, Usiello A (2017) Decreased free d-aspartate levels are linked to enhanced d-aspartate oxidase activity in the dorsolateral prefrontal cortex of schizophrenia patients. NPJ Schizophr 3:16. https://doi.org/10.1038/s41537-017-0015-7
Nuzzo T, Feligioni M, Cristino L, Pagano I, Marcelli S, Iannuzzi F, Imperatore R, D’Angelo L, Petrella C, Carella M, Pollegioni L, Sacchi S, Punzo D, De Girolamo P, Errico F, Canu N, Usiello A (2019a) Free d-aspartate triggers NMDA receptor-dependent cell death in primary cortical neurons and perturbs JNK activation, Tau phosphorylation, and protein SUMOylation in the cerebral cortex of mice lacking d-aspartate oxidase activity. Exp Neurol 317:51–65. https://doi.org/10.1016/j.expneurol.2019.02.014
Nuzzo T, Punzo D, Devoto P, Rosini E, Paciotti S, Sacchi S, Li Q, Thiolat ML, Vega C, Carella M, Carta M, Gardoni F, Calabresi P, Pollegioni L, Bezard E, Parnetti L, Errico F, Usiello A (2019b) The levels of the NMDA receptor co-agonist D-serine are reduced in the substantia nigra of MPTP-lesioned macaques and in the cerebrospinal fluid of Parkinson’s disease patients. Sci Rep 9(1):8898. https://doi.org/10.1038/s41598-019-45419-1
Nuzzo T, Miroballo M, Casamassa A, Mancini A, Gaetani L, Nistico R, Eusebi P, Katane M, Homma H, Calabresi P, Errico F, Parnetti L, Usiello A (2020a) Cerebrospinal fluid and serum d-serine concentrations are unaltered across the whole clinical spectrum of Alzheimer’s disease. Biochim Biophys Acta Proteins Proteom 18658(12):140537. https://doi.org/10.1016/j.bbapap.2020.140537
Nuzzo T, Sekine M, Punzo D, Miroballo M, Katane M, Saitoh Y, Galbusera A, Pasqualetti M, Errico F, Gozzi A, Mothet J-P, Homma H, Usiello A (2020) Dysfunctional d-aspartate metabolism in BTBR mouse model of idiopathic autism. Biochim Biophys Acta (BBA) Proteins Proteomics. https://doi.org/10.1016/j.bbapap.2020.140531
Olazarán J, Gil-de-Gómez L, Rodríguez-Martín A, Valentí-Soler M, Frades-Payo B, Marín-Muñoz J, Antúnez C, Frank-García A, Acedo-Jiménez C, Morlán-Gracia L, Petidier-Torregrossa R, Guisasola MC, Bermejo-Pareja F, Sánchez-Ferro Á, Pérez-Martínez DA, Manzano-Palomo S, Farquhar R, Rábano A, Calero M (2015) A blood-based, 7-metabolite signature for the early diagnosis of Alzheimer’s disease. J Alzheimer’s Dis 45(4):1157–1173. https://doi.org/10.3233/jad-142925
Palese F, Bonomi E, Nuzzo T, Benussi A, Mellone M, Zianni E, Cisani F, Casamassa A, Alberici A, Scheggia D, Padovani A, Marcello E, Di Luca M, Pittaluga A, Usiello A, Borroni B, Gardoni F (2020) Anti-GluA3 antibodies in frontotemporal dementia: effects on glutamatergic neurotransmission and synaptic failure. Neurobiol Aging 86:143–155. https://doi.org/10.1016/j.neurobiolaging.2019.10.015
Parsons Matthew P, Raymond Lynn A (2014) Extrasynaptic NMDA receptor involvement in central nervous system disorders. Neuron 82(2):279–293. https://doi.org/10.1016/j.neuron.2014.03.030
Pomara N, Stanley M, LeWitt PA, Galloway M, Singh R, Deptula D (1992) Increased CSF HVA response to arecoline challenge in Alzheimer’s disease. J Neural Transmission 90(1):53–65. https://doi.org/10.1007/bf01250518
Procter AW, Lowe SL, Palmer AM, Francis PT, Esiri MM, Stratmann GC, Najlerahim A, Patel AJ, Hunt A, Bowen DM (1988a) Topographical distribution of neurochemical changes in Alzheimer’s disease. J Neurol Sci 84(2–3):125–140. https://doi.org/10.1016/0022-510x(88)90118-9
Procter AW, Palmer AM, Francis PT, Lowe SL, Neary D, Murphy E, Doshi R, Bowen DM (1988b) Evidence of glutamatergic denervation and possible abnormal metabolism in Alzheimer’s disease. J Neurochem 50(3):790–802. https://doi.org/10.1111/j.1471-4159.1988.tb02983.x
Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362(4):329–344. https://doi.org/10.1056/nejmra0909142
Ramonet D, Rodríguez MJ, Fredriksson K, Bernal F, Mahy N (2004) In vivo neuroprotective adaptation of the glutamate/glutamine cycle to neuronal death. Hippocampus 14(5):586–594. https://doi.org/10.1002/hipo.10188
Reiber H (2001) Dynamics of brain-derived proteins in cerebrospinal fluid. Clin Chim Acta 310(2):173–186. https://doi.org/10.1016/s0009-8981(01)00573-3
Robinson SR (2000) Neuronal expression of glutamine synthetase in Alzheimer’s disease indicates a profound impairment of metabolic interactions with astrocytes. Neurochem Int 36(4–5):471–482. https://doi.org/10.1016/s0197-0186(99)00150-3
Robinson SR (2001) Changes in the cellular distribution of glutamine synthetase in Alzheimer’s disease. J Neurosci Res 66(5):972–980. https://doi.org/10.1002/jnr.10057
Rose Christopher F, Verkhratsky A, Parpura V (2013) Astrocyte glutamine synthetase: pivotal in health and disease. Biochem Soc Trans 41(6):1518–1524. https://doi.org/10.1042/bst20130237
Russell CL, Semerdjieva S, Empson RM, Austen BM, Beesley PW, Alifragis P (2012) Amyloid-β acts as a regulator of neurotransmitter release disrupting the interaction between synaptophysin and VAMP2. PLoS ONE 7(8):e43201–e43201. https://doi.org/10.1371/journal.pone.0043201
Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, Devidze N, Ho K, Yu G-Q, Palop JJ, Mucke L (2012) Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. Proc Natl Acad Sci U S A 109(42):E2895–E2903. https://doi.org/10.1073/pnas.1121081109
Sasaki H, Muramoto O, Kanazawa I, Arai H, Kosaka K, Iizuka R (1986) Regional distribution of amino acid transmitters in postmortem brains of presenile and senile dementia of Alzheimer type. Ann Neurol 19(3):263–269. https://doi.org/10.1002/ana.410190307
Scheltens P, Blennow K, Breteler MMB, de Strooper B, Frisoni GB, Salloway S, Van der Flier WM (2016) Alzheimer’s disease. Lancet 388(10043):505–517. https://doi.org/10.1016/s0140-6736(15)01124-1
Scott HL, Tannenberg AEG, Dodd PR (2002) Variant forms of neuronal glutamate transporter sites in Alzheimer’s disease cerebral cortex. J Neurochem 64(5):2193–2202. https://doi.org/10.1046/j.1471-4159.1995.64052193.x
Smith CC, Bowen DM, Francis PT, Snowden JS, Neary D (1985) Putative amino acid transmitters in lumbar cerebrospinal fluid of patients with histologically verified Alzheimer’s dementia. J Neurol Neurosurg Psychiatry 48(5):469–471. https://doi.org/10.1136/jnnp.48.5.469
Smith CD, Carney JM, Starke-Reed PE, Oliver CN, Stadtman ER, Floyd RA, Markesbery WR (1991) Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc Natl Acad Sci U S A 88(23):10540–10543. https://doi.org/10.1073/pnas.88.23.10540
Tarbit I, Perry EK, Perry RH, Blessed G, Tomlinson BE (1980) Hippocampal free amino acids in Alzheimer’s disease. J Neurochem 35(5):1246–1249. https://doi.org/10.1111/j.1471-4159.1980.tb07883.x
Teunissen CE, Petzold A, Bennett JL, Berven FS, Brundin L, Comabella M, Franciotta D, Frederiksen JL, Fleming JO, Furlan R, Hintzen RQ, Hughes SG, Johnson MH, Krasulova E, Kuhle J, Magnone MC, Rajda C, Rejdak K, Schmidt HK, van Pesch V, Waubant E, Wolf C, Giovannoni G, Hemmer B, Tumani H, Deisenhammer F (2009) A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking. Neurology 73(22):1914–1922. https://doi.org/10.1212/WNL.0b013e3181c47cc2
Timmer NM, Herbert MK, Claassen JA, Kuiperij HB, Verbeek MM (2015) Total glutamine synthetase levels in cerebrospinal fluid of Alzheimer’s disease patients are unchanged. Neurobiol Aging 36(3):1271–1273. https://doi.org/10.1016/j.neurobiolaging.2014.12.010
Tohgi H, Abe T, Takahashi S, Kimura M (1992) A selective reduction of excitatory amino acids in cerebrospinal fluid of patients with Alzheimer type dementia compared with vascular dementia of the Binswanger type. Neurosci Lett 141(1):5–8. https://doi.org/10.1016/0304-3940(92)90321-w
Trushina E, Mielke MM (2014) Recent advances in the application of metabolomics to Alzheimer’s disease. Biochim Biophys Acta 1842(8):1232–1239. https://doi.org/10.1016/j.bbadis.2013.06.014
Trushina E, Dutta T, Persson X-MT, Mielke MM, Petersen RC (2013) Identification of altered metabolic pathways in plasma and CSF in mild cognitive impairment and Alzheimer’s disease using metabolomics. PLoS ONE 8(5):e63644–e63644. https://doi.org/10.1371/journal.pone.0063644
Tumani H, Shen G, Peter JB, Bruck W (1999) Glutamine synthetase in cerebrospinal fluid, serum, and brain: a diagnostic marker for Alzheimer disease? Arch Neurol 56(10):1241–1246. https://doi.org/10.1001/archneur.56.10.1241
van der Lee SJ, Teunissen CE, Pool R, Shipley MJ, Teumer A, Chouraki V, Melo van Lent D, Tynkkynen J, Fischer K, Hernesniemi J, Haller T, Singh-Manoux A, Verhoeven A, Willemsen G, de Leeuw FA, Wagner H, van Dongen J, Hertel J, Budde K, Willems van Dijk K, Weinhold L, Ikram MA, Pietzner M, Perola M, Wagner M, Friedrich N, Slagboom PE, Scheltens P, Yang Q, Gertzen RE, Egert S, Li S, Hankemeier T, van Beijsterveldt CEM, Vasan RS, Maier W, Peeters CFW, Jörgen Grabe H, Ramirez A, Seshadri S, Metspalu A, Kivimäki M, Salomaa V, Demirkan A, Boomsma DI, van der Flier WM, Amin N, van Duijn CM (2018) Circulating metabolites and general cognitive ability and dementia: evidence from 11 cohort studies. Alzheimer’s Dementia 14(6):707–722. https://doi.org/10.1016/j.jalz.2017.11.012
Vanderstichele H, Bibl M, Engelborghs S, Le Bastard N, Lewczuk P, Molinuevo JL, Parnetti L, Perret-Liaudet A, Shaw LM, Teunissen C, Wouters D, Blennow K (2012) Standardization of preanalytical aspects of cerebrospinal fluid biomarker testing for Alzheimer’s disease diagnosis: a consensus paper from the Alzheimer’s biomarkers standardization initiative. Alzheimers Dement 8(1):65–73. https://doi.org/10.1016/j.jalz.2011.07.004
Verret L, Mann EO, Hang GB, Barth AMI, Cobos I, Ho K, Devidze N, Masliah E, Kreitzer AC, Mody I, Mucke L, Palop JJ (2012) Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell 149(3):708–721. https://doi.org/10.1016/j.cell.2012.02.046
Wang R, Reddy PH (2017) Role of glutamate and NMDA receptors in Alzheimer’s disease. J Alzheimers Dis 57(4):1041–1048. https://doi.org/10.3233/JAD-160763
Wang G, Zhou Y, Huang F-J, Tang H-D, Xu X-H, Liu J-J, Wang Y, Deng Y-L, Ren R-J, Xu W, Ma J-F, Zhang Y-N, Zhao A-H, Chen S-D, Jia W (2014) Plasma metabolite profiles of Alzheimer’s disease and mild cognitive impairment. J Proteome Res 13(5):2649–2658. https://doi.org/10.1021/pr5000895
Yu A, Lau AY (2018) Glutamate and glycine binding to the NMDA receptor. Structure 26(7):1035-1043.e1032. https://doi.org/10.1016/j.str.2018.05.004
Zádori D, Veres G, Szalárdy L, Klivényi P, Toldi J, Vécsei L (2014) Glutamatergic dysfunctioning in Alzheimer’s disease and related therapeutic targets. J Alzheimer’s Dis 42(s3):S177–S187. https://doi.org/10.3233/jad-132621
Zhou Y, Danbolt NC (2014) Glutamate as a neurotransmitter in the healthy brain. J Neural Transm (Vienna) 121(8):799–817. https://doi.org/10.1007/s00702-014-1180-8
Acknowledgements
Post-mortem human brain samples were provided by The Netherlands Brain Bank (Netherlands Institute for Neuroscience, Amsterdam, open access: www.brainbank.nl). AU and TN were supported by a grant from Fondazione Cariplo (Project nr 2017-0575). We thank Giada Torresi for her valuable technical support.
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Nuzzo, T., Mancini, A., Miroballo, M. et al. High performance liquid chromatography determination of l-glutamate, l-glutamine and glycine content in brain, cerebrospinal fluid and blood serum of patients affected by Alzheimer’s disease. Amino Acids 53, 435–449 (2021). https://doi.org/10.1007/s00726-021-02943-7
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DOI: https://doi.org/10.1007/s00726-021-02943-7