Age-dependent decrease in glutamine synthetase expression in the hippocampal astroglia of the triple transgenic Alzheimer's disease mouse model: mechanism for deficient glutamatergic transmission?

Molecular Neurodegeneration

José J Rodríguez¹  Alexei Verkhratsky¹  Harun N Noristani²  Markel Olabarria² 

[1] Department of Neurosciences, University of the Basque Country UPV/EHU, 48940, Leioa, Spain;Faculty of Life Sciences, The University of Manchester, Manchester, UK

关键词: plasticity;    hippocampus;    excitotoxicity;    amyloid beta;    GFAP;    glutamine synthetase;    Alzheimer's disease;    Astroglia;   

Others  :  865728
DOI  :  10.1186/1750-1326-6-55

 received in 2010-10-26, accepted in 2011-07-30,  发布年份 2011

【 摘 要 】

Astrocytes are fundamental for brain homeostasis and the progression and outcome of many neuropathologies including Alzheimer's disease (AD). In the triple transgenic mouse model of AD (3xTg-AD) generalised hippocampal astroglia atrophy precedes a restricted and specific β-amyloid (Aβ) plaque-related astrogliosis. Astrocytes are critical for CNS glutamatergic transmission being the principal elements of glutamate homeostasis through maintaining its synthesis, uptake and turnover via glutamate-glutamine shuttle. Glutamine synthetase (GS), which is specifically expressed in astrocytes, forms glutamine by an ATP-dependent amination of glutamate. Here, we report changes in GS astrocytic expression in two major cognitive areas of the hippocampus (the dentate gyrus, DG and the CA1) in 3xTg-AD animals aged between 9 and 18 months. We found a significant reduction in N_v (number of cell/mm³) of GS immunoreactive (GS-IR) astrocytes starting from 12 months (28.59%) of age in the DG, and sustained at 18 months (31.65%). CA1 decrease of GS-positive astrocytes N_v (33.26%) occurs at 18 months. This N_v reduction of GS-IR astrocytes is paralleled by a decrease in overall GS expression (determined by its optical density) that becomes significant at 18 months (21.61% and 19.68% in DG and CA1, respectively). GS-IR N_v changes are directly associated with the presence of Aβ deposits showing a decrease of 47.92% as opposed to 23.47% in areas free of Aβ. These changes in GS containing astrocytes and GS-immunoreactivity indicate AD-related impairments of glutamate homeostatic system, at the advanced and late stages of the disease, which may affect the efficacy of glutamatergic transmission in the diseased brain that may contribute to the cognitive deficiency.

【 授权许可】

   
2011 Olabarria et al; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Pellerin L, Bouzier-Sore AK, Aubert A, Serres S, Merle M, Costalat R, Magistretti PJ: Activity-dependent regulation of energy metabolism by astrocytes: an update. Glia 2007, 55:1251-1262.
• [2]Magistretti PJ: Role of glutamate in neuron-glia metabolic coupling. Am J Clin Nutr 2009, 90:875S-880S.
• [3]Simard M, Nedergaard M: The neurobiology of glia in the context of water and ion homeostasis. Neuroscience 2004, 129:877-896.
• [4]Kofuji P, Newman EA: Potassium buffering in the central nervous system. Neuroscience 2004, 129:1045-1056.
• [5]Verkhratsky A, Parpura V, Rodriguez JJ: Where the thoughts dwell: The physiology of neuronal-glial "diffuse neural net". Brain Res Rev 2011, 66:133-151.
• [6]Halassa MM, Haydon PG: Integrated brain circuits: astrocytic networks modulate neuronal activity and behavior. Annu Rev Physiol 2010, 72:335-355.
• [7]Perea G, Navarrete M, Araque A: Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci 2009, 32:421-431.
• [8]Wilhelmsson U, Bushong EA, Price DL, Smarr BL, Phung V, Terada M, Ellisman MH, Pekny M: Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury. Proc Natl Acad Sci USA 2006, 103:17513-17518.
• [9]Danbolt NC: Glutamate uptake. Prog Neurobiol 2001, 65:1-105.
• [10]Grosche J, Matyash V, Moller T, Verkhratsky A, Reichenbach A, Kettenmann H: Microdomains for neuron-glia interaction: parallel fiber signaling to Bergmann glial cells. Nat Neurosci 1999, 2:139-143.
• [11]Araque A, Parpura V, Sanzgiri RP, Haydon PG: Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 1999, 22:208-215.
• [12]Kvamme E: Synthesis of glutamate and its regulation. Prog Brain Res 1998, 116:73-85.
• [13]McKenna MC: The glutamate-glutamine cycle is not stoichiometric: fates of glutamate in brain. J Neurosci Res 2007, 85:3347-3358.
• [14]Kirischuk S, Kettenmann H, Verkhratsky A: Membrane currents and cytoplasmic sodium transients generated by glutamate transport in Bergmann glial cells. Pflugers Arch 2007, 454:245-252.
• [15]Gras G, Samah B, Hubert A, Leone C, Porcheray F, Rimaniol AC: EAAT expression by macrophages and microglia: still more questions than answers. Amino Acids 2011.
• [16]Takasaki C, Yamasaki M, Uchigashima M, Konno K, Yanagawa Y, Watanabe M: Cytochemical and cytological properties of perineuronal oligodendrocytes in the mouse cortex. Eur J Neurosci 2010, 32:1326-1336.
• [17]Deitmer JW, Broer A, Broer S: Glutamine efflux from astrocytes is mediated by multiple pathways. J Neurochem 2003, 87:127-135.
• [18]Walton HS, Dodd PR: Glutamate-glutamine cycling in Alzheimer's disease. Neurochem Int 2007, 50:1052-1066.
• [19]Choi DW: Excitotoxic cell death. J Neurobiol 1992, 23:1261-1276.
• [20]Giaume C, Kirchhoff F, Matute C, Reichenbach A, Verkhratsky A: Glia: the fulcrum of brain diseases. Cell Death Differ 2007, 14:1324-1335.
• [21]Nedergaard M, Rodriguez JJ, Verkhratsky A: Glial calcium and diseases of the nervous system. Cell Calcium 2010, 47:140-149.
• [22]Heneka MT, Rodriguez JJ, Verkhratsky A: Neuroglia in neurodegeneration. Brain Res Rev 2010, 63:189-211.
• [23]Verkhratsky A, Olabarria M, Noristani HN, Yeh CY, Rodriguez JJ: Astrocytes in Alzheimer's disease. Neurotherapeutics 2010, 7:399-412.
• [24]Samland H, Huitron-Resendiz S, Masliah E, Criado J, Henriksen SJ, Campbell IL: Profound increase in sensitivity to glutamatergic- but not cholinergic agonist-induced seizures in transgenic mice with astrocyte production of IL-6. J Neurosci Res 2003, 73:176-187.
• [25]Aloisi F, Care A, Borsellino G, Gallo P, Rosa S, Bassani A, Cabibbo A, Testa U, Levi G, Peschle C: Production of hemolymphopoietic cytokines (IL-6, IL-8, colony-stimulating factors) by normal human astrocytes in response to IL-1 beta and tumor necrosis factor-alpha. J Immunol 1992, 149:2358-2366.
• [26]Nedergaard M, Dirnagl U: Role of glial cells in cerebral ischemia. Glia 2005, 50:281-286.
• [27]Walsh DM, Selkoe DJ: A beta oligomers - a decade of discovery. J Neurochem 2007, 101:1172-1184.
• [28]Braak E, Griffing K, Arai K, Bohl J, Bratzke H, Braak H: Neuropathology of Alzheimer's disease: what is new since A. Alzheimer? Eur Arch Psychiatry Clin Neurosci 1999, 249(Suppl 3):14-22.
• [29]Yankner BA: Mechanisms of neuronal degeneration in Alzheimer's disease. Neuron 1996, 16:921-932.
• [30]Pekny M, Nilsson M: Astrocyte activation and reactive gliosis. Glia 2005, 50:427-434.
• [31]Noristani HN, Olabarria M, Verkhratsky A, Rodriguez JJ: Serotonin fibre sprouting and increase in serotonin transporter immunoreactivity in the CA1 area of hippocampus in a triple transgenic mouse model of Alzheimer's disease. Eur J Neurosci 2010, 32:71-79.
• [32]Olabarria M, Noristani HN, Verkhratsky A, Rodriguez JJ: Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer's disease. Glia 2010, 58:831-838.
• [33]Rodriguez JJ, Olabarria M, Chvatal A, Verkhratsky A: Astroglia in dementia and Alzheimer's disease. Cell Death Differ 2009, 16:378-385.
• [34]Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM: Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease. Neurobiol Aging 2003, 24:1063-1070.
• [35]Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM: Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 2003, 39:409-421.
• [36]Rodriguez JJ, Jones VC, Tabuchi M, Allan SM, Knight EM, LaFerla FM, Oddo S, Verkhratsky A: Impaired adult neurogenesis in the dentate gyrus of a triple transgenic mouse model of Alzheimer's disease. PLoS One 2008, 3:e2935.
• [37]Rodriguez JJ, Jones VC, Verkhratsky A: Impaired cell proliferation in the subventricular zone in an Alzheimer's disease model. Neuroreport 2009, 20:907-912.
• [38]Paxinos G, Franklin KBJ: The mouse brain in stereotaxic coordinates. Elsevier: Academic Press; 2004.
• [39]Wilhelmsson U, Li L, Pekna M, Berthold CH, Blom S, Eliasson C, Renner O, Bushong E, Ellisman M, Morgan TE, Pekny M: Absence of glial fibrillary acidic protein and vimentin prevents hypertrophy of astrocytic processes and improves post-traumatic regeneration. J Neurosci 2004, 24:5016-5021.
• [40]Eng LF, Ghirnikar RS, Lee YL: Glial fibrillary acidic protein: GFAP-thirty-one years (1969-2000). Neurochem Res 2000, 25:1439-1451.
• [41]Aksenov MY, Aksenova MV, Butterfield DA, Hensley K, Vigo-Pelfrey C, Carney JM: Glutamine synthetase-induced enhancement of beta-amyloid peptide A beta (1-40) neurotoxicity accompanied by abrogation of fibril formation and A beta fragmentation. J Neurochem 1996, 66:2050-2056.
• [42]Hensley K, Hall N, Subramaniam R, Cole P, Harris M, Aksenov M, Aksenova M, Gabbita SP, Wu JF, Carney JM, et al.: Brain regional correspondence between Alzheimer's disease histopathology and biomarkers of protein oxidation. J Neurochem 1995, 65:2146-2156.
• [43]Cordero MI, Rodriguez JJ, Davies HA, Peddie CJ, Sandi C, Stewart MG: Chronic restraint stress down-regulates amygdaloid expression of polysialylated neural cell adhesion molecule. Neuroscience 2005, 133:903-910.
• [44]Alzheimer A: Beiträge zur Kenntnis der pathologischen Neuroglia und ihrer Beziehungen zu den Abbauvorgängen im Nervengewebe. In Histologische und Histopathologische Arbeiten über die Grosshirnrinde mit besonderer Berücksichtigung der pathologischen Anatomie der Geisteskrankheiten Jena. Verlag von Gustav Fischer; 1910:401-562.
• [45]Sullivan SM, Lee A, Bjorkman ST, Miller SM, Sullivan RK, Poronnik P, Colditz PB, Pow DV: Cytoskeletal anchoring of GLAST determines susceptibility to brain damage: an identified role for GFAP. J Biol Chem 2007, 282:29414-29423.
• [46]Hughes EG, Maguire JL, McMinn MT, Scholz RE, Sutherland ML: Loss of glial fibrillary acidic protein results in decreased glutamate transport and inhibition of PKA-induced EAAT2 cell surface trafficking. Brain Res Mol Brain Res 2004, 124:114-123.
• [47]Pekny M, Eliasson C, Siushansian R, Ding M, Dixon SJ, Pekna M, Wilson JX, Hamberger A: The impact of genetic removal of GFAP and/or vimentin on glutamine levels and transport of glucose and ascorbate in astrocytes. Neurochem Res 1999, 24:1357-1362.
• [48]Weir MD, Thomas DG: Effect of dexamethasone on glutamine synthetase and glial fibrillary acidic protein in normal and transformed astrocytes. Clin Neuropharmacol 1984, 7:303-306.
• [49]Fuhrmann M, Bittner T, Jung CK, Burgold S, Page RM, Mitteregger G, Haass C, LaFerla FM, Kretzschmar H, Herms J: Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease. Nat Neurosci 2010, 13:411-413.
• [50]Le Prince G, Delaere P, Fages C, Lefrancois T, Touret M, Salanon M, Tardy M: Glutamine synthetase (GS) expression is reduced in senile dementia of the Alzheimer type. Neurochem Res 1995, 20:859-862.
• [51]Robinson SR: Neuronal expression of glutamine synthetase in Alzheimer's disease indicates a profound impairment of metabolic interactions with astrocytes. Neurochem Int 2000, 36:471-482.
• [52]Robinson SR: Changes in the cellular distribution of glutamine synthetase in Alzheimer's disease. J Neurosci Res 2001, 66:972-980.
• [53]Lievens JC, Woodman B, Mahal A, Spasic-Boscovic O, Samuel D, Kerkerian-Le Goff L, Bates GP: Impaired glutamate uptake in the R6 Huntington's disease transgenic mice. Neurobiol Dis 2001, 8:807-821.
• [54]Jacob CP, Koutsilieri E, Bartl J, Neuen-Jacob E, Arzberger T, Zander N, Ravid R, Roggendorf W, Riederer P, Grunblatt E: Alterations in expression of glutamatergic transporters and receptors in sporadic Alzheimer's disease. J Alzheimers Dis 2007, 11:97-116.
• [55]Castegna A, Aksenov M, Aksenova M, Thongboonkerd V, Klein JB, Pierce WM, Booze R, Markesbery WR, Butterfield DA: Proteomic identification of oxidatively modified proteins in Alzheimer's disease brain. Part I: creatine kinase BB, glutamine synthase, and ubiquitin carboxy-terminal hydrolase L-1. Free Radic Biol Med 2002, 33:562-571.
• [56]Burbaeva G, Boksha IS, Tereshkina EB, Savushkina OK, Starodubtseva LI, Turishcheva MS: Glutamate metabolizing enzymes in prefrontal cortex of Alzheimer's disease patients. Neurochem Res 2005, 30:1443-1451.