Amino Acids

, Volume 32, Issue 2, pp 213–224

Free amino acid and dipeptide changes in the body fluids from Alzheimer’s disease subjects

  • A. N. Fonteh
  • R. J. Harrington
  • A. Tsai
  • P. Liao
  • M. G. Harrington
Article

Summary.

Our aim was to determine changes in free amino acid (FAA) and dipeptide (DP) concentrations in probable Alzheimer’s disease (pAD) subjects compared with control (CT) subjects using liquid chromatography and electrospray ionization tandem mass spectrometry (LCMS2). We recruited gender- and age-matched study participants based on neurological and neuropsychological assessments. We measured FAAs and DPs in cerebrospinal fluid (CSF), plasma and urine using LCMS2 with selected reaction monitoring (SRM). Imidazole-containing FAAs (histidine, methyl-histidine), catecholamines (L-DOPA and dopamine), citrulline, ornithine, glycine and antioxidant DPs (carnosine and anserine) accounted for the major changes between CT and pAD. Carnosine levels were significantly lower in pAD (328.4 ± 91.31 nmol/dl) than in CT plasma (654.23 ± 100.61 nmol/dl). In contrast, L-DOPA levels were higher in pAD (1400.84 ± 253.68) than CT (513.10 ± 121.61 nmol/dl) plasma. These data underscore the importance of FAA and DP metabolism in the pathogenesis of AD. Since our data show changes in antioxidants, neurotransmitters and their precursors, or FAA associated with urea metabolism in pAD compared with CT, we propose that manipulation of these metabolic pathways may be important in preventing AD progression.

Keywords: Amino acids – Dipeptides – Tandem mass spectrometry – Cerebrospinal fluid – Plasma – Alzheimer’s disease 

Abbreviations:

CT

control study participants

pAD

probable Alzheimer’s disease study participants

CT_M

control male

CT_F

control female

pAD_M

pAD male

pAD_F

pAD female

MMSE

mini-mental state examination

ADAS-cog

Alzheimer’s Disease Assessment Scale- cognitive subscale

LCMS2

liquid chromatography electrospray ionization tandem mass spectrometry

SRM

selected reaction monitoring

FAA

free amino acid

DP

dipeptide

GABA

γ-aminobutyric acid

βABA

β-aminobutyric acid

ABA

α-aminobutyric acid

DABA

2,4-diaminobutyric acid

DOPA

3,4-dihydroxyphenyl-L-alanine

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Advokat, C, Pellegrin, AI 1992Excitatory amino acids and memory: evidence from research on Alzheimer’s disease and behavioral pharmacologyNeurosci Biobehav Rev161324PubMedCrossRefGoogle Scholar
  2. Agid, Y, Pollak, P, Bonnet, AM, Signoret, JL, Lhermitte, F 1979Bromocriptine associated with a peripheral dopamine blocking agent in treatment of Parkinson’s diseaseLancet1570572PubMedCrossRefGoogle Scholar
  3. Barbanti, P, Fabbrini, G, Ricci, A, Bruno, G, Cerbo, R, Bronzetti, E, Amenta, F, Luigi, LG 2000Reduced density of dopamine D2-like receptors on peripheral blood lymphocytes in Alzheimer’s diseaseMech Ageing Dev1206575PubMedCrossRefGoogle Scholar
  4. Barili, P, Bronzetti, E, Felici, L, Ferrante, F, Ricci, A, Zaccheo, D, Amenta, F 1996Age-dependent changes in the expression of dopamine receptor subtypes in human peripheral blood lymphocytesJ Neuroimmunol714550PubMedCrossRefGoogle Scholar
  5. Berl, S, Waelsch, H 1958Determination of glutamic acid, glutamine, glutathione and gamma-aminobutyric acid and their distribution in brain tissueJ Neurochem3161169PubMedCrossRefGoogle Scholar
  6. Boldyrev, AA, Gallant, SC, Sukhich, GT 1999Carnosine, the protective, anti-aging peptideBiosci Rep19581587PubMedCrossRefGoogle Scholar
  7. Bolme, P, Fuxe, K, Hokfelt, T, Goldstein, M 1977Studies on the role of dopamine in cardiovascular and respiratory control: central versus peripheral mechanismsAdv Biochem Psychopharmacol16281290PubMedGoogle Scholar
  8. Bonfanti, L, Peretto, P, De Marchis, S, Fasolo, A 1999Carnosine-related dipeptides in the mammalian brainProg Neurobiol59333353PubMedCrossRefGoogle Scholar
  9. Bowen, D 1990The cholinergic system and the excitatory amino acids in Alzheimer’s diseaseActa Neurol Scand [Suppl]1291516Google Scholar
  10. Caronti, B, Tanda, G, Colosimo, C, Ruggieri, S, Calderaro, C, Palladini, G, Pontieri, FE, Di Chiara, G 1999Reduced dopamine in peripheral blood lymphocytes in Parkinson’s diseaseNeuroreport1029072910PubMedCrossRefGoogle Scholar
  11. Chapman, PF, Falinska, AM, Knevett, SG, Ramsay, MF 2001Genes, models and Alzheimer’s diseaseTrends Genet17254261PubMedCrossRefGoogle Scholar
  12. Corsini, GU, Del Zompo, M, Tocco, F, Arca, P, Gessa, GL 1980Drugs acting on dopamine receptors: usefulness of a peripheral blocker in Parkinson’s diseasePharmacol Res Commun12699707PubMedCrossRefGoogle Scholar
  13. Csernansky, JG, Bardgett, ME, Sheline, YI, Morris, JC, Olney, JW 1996CSF excitatory amino acids and severity of illness in Alzheimer’s diseaseNeurology4617151720PubMedGoogle Scholar
  14. Cummings, JL, Jeste, DV 1999Alzheimer’s disease and its management in the year 2010Psychiatr Serv5011731177PubMedGoogle Scholar
  15. Cummings, JL, Knopman, D 1999Advances in the treatment of behavioral disturbances in Alzheimer’s diseaseNeurology53899901PubMedGoogle Scholar
  16. Cummings, JL, Vinters, HV, Cole, GM, Khachaturian, ZS 1998Alzheimer’s disease: etiologies, pathophysiology, cognitive reserve, and treatment opportunitiesNeurology51S2S17PubMedGoogle Scholar
  17. D’Andrea, G, Cananzi, AR, Joseph, R, Morra, M, Zamberlan, F, Ferro, MF, Grunfeld, S, Welch, KM 1991Platelet glycine, glutamate and aspartate in primary headacheCephalalgia11197200PubMedCrossRefGoogle Scholar
  18. Date, I, Ohmoto, T 1996Neural transplantation and trophic factors in Parkinson’s disease: special reference to chromaffin cell grafting, NGF support from pretransected peripheral nerve, and encapsulated dopamine-secreting cell graftingExp Neurol137333344PubMedCrossRefGoogle Scholar
  19. Doraiswamy, PM, Leon, J, Cummings, JL, Marin, D, Neumann, PJ 2002Prevalence and impact of medical comorbidity in Alzheimer’s diseaseJ Gerontol A Biol Sci Med Sci57M173M177PubMedGoogle Scholar
  20. Fitzpatrick, PF 1991Studies of the rate-limiting step in the tyrosine hydroxylase reaction: alternate substrates, solvent isotope effects, and transition-state analoguesBiochemistry3063866391PubMedCrossRefGoogle Scholar
  21. Fonnum, F 1984Glutamate: a neurotransmitter in mammalian brainJ Neurochem42111PubMedCrossRefGoogle Scholar
  22. Fonteh, AN, Harrington, JR, Harrington, MG 2007Quantification of free amino acids and dipeptides using isotope dilution liquid chromatography electrospray tandem mass spectrometryAmino Acids32203212PubMedGoogle Scholar
  23. Gallai, V, Alberti, A, Gallai, B, Coppola, F, Floridi, A, Sarchielli, P 2003Glutamate and nitric oxide pathway in chronic daily headache: evidence from cerebrospinal fluidCephalalgia23166174PubMedCrossRefGoogle Scholar
  24. Glavin, GB, Hall, AM 1995Central and peripheral dopamine D1/DA1 receptor modulation of gastric secretion and experimental gastric mucosal injuryGen Pharmacol2612771279PubMedGoogle Scholar
  25. Goldstein, DS, Mezey, E, Yamamoto, T, Aneman, A, Friberg, P, Eisenhofer, G 1995Is there a third peripheral catecholaminergic system? Endogenous dopamine as an autocrine/paracrine substance derived from plasma DOPA and inactivated by conjugationHypertens Res18S93S99PubMedGoogle Scholar
  26. Gould, BS, Woessner, JF 1957Biosynthesis of collagen; the influence of ascorbic acid on the proline, hydroxyproline, glycine, and collagen content of regenerating guinea pig skinJ Biol Chem226289300PubMedGoogle Scholar
  27. Greenamyre, JT, Young, AB 1989Excitatory amino acids and Alzheimer’s diseaseNeurobiol Aging10593602PubMedCrossRefGoogle Scholar
  28. Grunblatt, E, Mandel, S, Youdim, MB 2000Neuroprotective strategies in Parkinson’s disease using the models of 6-hydroxydopamine and MPTPAnn NY Acad Sci899262273PubMedCrossRefGoogle Scholar
  29. Hipkiss, AR 2002Could carnosine be a naturally-occurring scavenger for acrolein and other reactive aldehydes in the brain?Neurobiol Aging23645646PubMedCrossRefGoogle Scholar
  30. Husek, P 1998Chloroformates in gas chromatography as general purpose derivatizing agentsJ Chromatogr B Biomed Sci Appl7175791PubMedCrossRefGoogle Scholar
  31. Knopman, DS, DeKosky, ST, Cummings, JL, Chui, H, Corey-Bloom, J, Relkin, N, Small, GW, Miller, B, Stevens, JC 2001Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of NeurologyNeurology5611431153PubMedGoogle Scholar
  32. Kohen, R, Yamamoto, Y, Cundy, KC, Ames, BN 1988Antioxidant activity of carnosine, homocarnosine, and anserine present in muscle and brainProc Natl Acad Sci USA8531753179PubMedCrossRefGoogle Scholar
  33. Kohli, JD 1990Peripheral dopamine receptorsAm J Hypertens325S28SPubMedGoogle Scholar
  34. Kohli, JD, McNay, JL, Rajfer, SI, Murphy, MB 1991Peripheral dopamine receptors in cardiovascular therapy. The legacy of Leon Goldberg (1927–1989)Hypertension17700706PubMedGoogle Scholar
  35. Kuchel, O 1999Peripheral dopamine in hypertension and associated conditionsJ Hum Hypertens13605615PubMedCrossRefGoogle Scholar
  36. Lackovic, Z, Relja, M, Neff, NH 1982Catabolism of endogenous dopamine in peripheral tissues: is there an independent role for dopamine in peripheral neurotransmission?J Neurochem3814531458PubMedCrossRefGoogle Scholar
  37. Lee, WJ, Hawkins, RA, Vina, JR, Peterson, DR 1998Glutamine transport by the blood-brain barrier: a possible mechanism for nitrogen removalAm J Physiol274C1101C1107PubMedGoogle Scholar
  38. Liu, Z, Zhang, J, Fei, J, Guo, L 2001A novel mechanism of dopamine neurotoxicity involving the peripheral extracellular and the plasma membrane dopamine transporterNeuroreport1232933297PubMedCrossRefGoogle Scholar
  39. Marazziti, D, Hollander, E, Lensi, P, Ravagli, S, Cassano, GB 1992Peripheral markers of serotonin and dopamine function in obsessive-compulsive disorderPsychiatry Res424151PubMedCrossRefGoogle Scholar
  40. Marchis, SD, Modena, C, Peretto, P, Migheli, A, Margolis, FL, Fasolo, A 2000Carnosine-related dipeptides in neurons and gliaBiochemistry (Mosc.)65824833Google Scholar
  41. Markesbery, WR, Carney, JM 1999Oxidative alterations in Alzheimer’s diseaseBrain Pathol9133146PubMedCrossRefGoogle Scholar
  42. Mayerhofer, A, Hemmings, HC,Jr, Snyder, GL, Greengard, P, Boddien, S, Berg, U, Brucker, C 1999Functional dopamine-1 receptors and DARPP-32 are expressed in human ovary and granulosa luteal cells in vitroJ Clin Endocrinol Metab84257264PubMedCrossRefGoogle Scholar
  43. McKhann, G, Drachman, D, Folstein, M, Katzman, R, Price, D, Stadlan, EM 1984Clinical 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 DiseaseNeurology34939944PubMedGoogle Scholar
  44. Memo, M, Missale, C, Carruba, MO, Spano, PF 1986Pharmacology and biochemistry of dopamine receptors in the central nervous system and peripheral tissueJ Neural Transm [Suppl]221932Google Scholar
  45. Mendiondo, MS, Ashford, JW, Kryscio, RJ, Schmitt, FA 2000Modelling mini mental state examination changes in Alzheimer’s diseaseStat Med1916071616PubMedCrossRefGoogle Scholar
  46. Molina, JA, Jimenez-Jimenez, FJ, Vargas, C, Gomez, P, de Bustos, F, Orti-Pareja, M, Tallon-Barranco, A, Benito-Leon, J, Arenas, J, Enriquez-de-Salamanca, R 1998Cerebrospinal fluid levels of non-neurotransmitter amino acids in patients with Alzheimer’s diseaseJ Neural Transm105279286PubMedCrossRefGoogle Scholar
  47. Murphy, MB, Murray, C, Shorten, GD 2001Fenoldopam: a selective peripheral dopamine-receptor agonist for the treatment of severe hypertensionN Engl J Med34515481557PubMedCrossRefGoogle Scholar
  48. Nedergaard, M, Takano, T, Hansen, AJ 2002Beyond the role of glutamate as a neurotransmitterNat Rev Neurosci3748755PubMedCrossRefGoogle Scholar
  49. Perry, TL, Yong, VW, Bergeron, C, Hansen, S, Jones, K 1987Amino acids, glutathione, and glutathione transferase activity in the brains of patients with Alzheimer’s diseaseAnn Neurol21331336PubMedCrossRefGoogle Scholar
  50. Pomara, N, Singh, R, Deptula, D, Chou, JC, Schwartz, MB, LeWitt, PA 1992Glutamate and other CSF amino acids in Alzheimer’s diseaseAm J Psychiatry149251254PubMedGoogle Scholar
  51. Preston, JE, Hipkiss, AR, Himsworth, DT, Romero, IA, Abbott, JN 1998Toxic effects of beta-amyloid(25–35) on immortalised rat brain endothelial cell: protection by carnosine, homocarnosine and beta-alanineNeurosci Lett242105108PubMedCrossRefGoogle Scholar
  52. Sandbrink, R, Hartmann, T, Masters, CL, Beyreuther, K 1996Genes contributing to Alzheimer’s diseaseMol Psychiatry12740PubMedGoogle Scholar
  53. Schofield, P 1996Glycine: the other inhibitory neurotransmitterAlcohol Clin Exp Res20219A223APubMedCrossRefGoogle Scholar
  54. Singh, AN, Barlas, C, Saeedi, H, Mishra, RK 2003Effect of loxapine on peripheral dopamine-like and serotonin receptors in patients with schizophreniaJ Psychiatry Neurosci283947PubMedGoogle Scholar
  55. Snider, SR 1975Letter: Release of peripheral dopamine during stressLancet2868PubMedCrossRefGoogle Scholar
  56. Storga, D, Vrecko, K, Birkmayer, JG, Reibnegger, G 1996Monoaminergic neurotransmitters, their precursors and metabolites in brains of Alzheimer patientsNeurosci Lett2032932PubMedCrossRefGoogle Scholar
  57. Stuerenburg, HJ 2000The roles of carnosine in aging of skeletal muscle and in neuromuscular diseasesBiochemistry (Mosc.)65862865Google Scholar
  58. Stvolinskii, SL, Fedorova, TN, Yuneva, MO, Boldyrev, AA 2003Protective effect of carnosine on Cu, Zn-superoxide dismutase during impaired oxidative metabolism in the brain in vivoBull Exp Biol Med135130132PubMedCrossRefGoogle Scholar
  59. Vogel, WH, Heginbothom, SD, Boehme, DH 1975Glutamic acid decarboxylase, glutamine synthase and glutamic acid dehydrogenase in various areas of human brainBrain Res88131135PubMedCrossRefGoogle Scholar
  60. Walker, FA 2004Models of the bis-histidine-ligated electron-transferring cytochromes. Comparative geometric and electronic structure of low-spin ferro- and ferrihemesChem Rev104589615PubMedCrossRefGoogle Scholar
  61. Wang, D, Chalk, JB, Rose, SE, de Zubicaray, G, Cowin, G, Galloway, GJ, Barnes, D, Spooner, D, Doddrell, DM, Semple, J 2002MR image-based measurement of rates of change in volumes of brain structures. Part II: application to a study of Alzheimer’s disease and normal agingMagn Reson Imaging204148PubMedCrossRefGoogle Scholar
  62. Weinberg, RJ 1999Glutamate: an excitatory neurotransmitter in the mammalian CNSBrain Res Bull50353354PubMedCrossRefGoogle Scholar
  63. Weyer, G, Erzigkeit, H, Kanowski, S, Ihl, R, Hadler, D 1997Alzheimer’s Disease Assessment Scale: reliability and validity in a multicenter clinical trialInt Psychogeriatr9123138PubMedCrossRefGoogle Scholar
  64. White, NM, Packard, MG, Seamans, J 1993Memory enhancement by post-training peripheral administration of low doses of dopamine agonists: possible autoreceptor effectBehav Neural Biol59230241PubMedCrossRefGoogle Scholar
  65. Yoneda, S, Tomioka, H, Fukuyama, M, Lee, LC, Iyota, I, Okajima, H, Inoue, A, Sasaki, S, Takeda, K, Takahashi, H 1985Peripheral origin of plasma dopamineJpn Circ J4910281034PubMedGoogle Scholar
  66. Zhang, J, Kravtsov, V, Amarnath, V, Picklo, MJ, Graham, DG, Montine, TJ 2000Enhancement of dopaminergic neurotoxicity by the mercapturate of dopamine: relevance to Parkinson’s diseaseJ Neurochem74970978PubMedCrossRefGoogle Scholar
  67. Zuo, SS, Lundahl, P 2000A micro-Bradford membrane protein assayAnal Biochem284162164PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • A. N. Fonteh
    • 1
  • R. J. Harrington
    • 1
  • A. Tsai
    • 1
  • P. Liao
    • 1
  • M. G. Harrington
    • 1
  1. 1.Molecular Neurology Program, Huntington Medical Research InstitutesPasadenaU.S.A.

Personalised recommendations