Journal of Neuroimmune Pharmacology

, Volume 4, Issue 4, pp 389–398 | Cite as

Microglia in ALS: The Good, The Bad, and The Resting

  • Jenny S. Henkel
  • David R. Beers
  • Weihua Zhao
  • Stanley H. Appel
Invited Review


Inflammation, including microglial activation and T cell infiltration, is a neuropathological hallmark of amyotrophic lateral sclerosis (ALS), a rapidly progressing neurodegenerative disease. The identification of mutations in the gene for Cu2+/Zn2+ superoxide dismutase (SOD1) from patients with an inherited form of ALS enabled the creation of transgenic mice overexpressing mutant forms of SOD1 (mSOD1) which develop a motoneuron disease that resembles the disease seen in ALS patients. These transgenic mice display similar inflammatory reactions at sites of motoneuron injury as detected in ALS patients, enabling the observation that this inflammation is not simply a late consequence of motoneuron degeneration, but actively contributes to the balance between neuroprotection and neurotoxicity. The microglial and T cell activation states influence the rate of disease progression. Initially, microglia and T cells can slow disease progression, while they may later contribute to the acceleration of disease. Accumulation of intracellular and extracellular misfolded mSOD1 may be key events regulating the transformation from neuroprotective alternatively activated M2 microglia to cytotoxic classically activated M1 microglia. Intracellular and extracellular mSOD1 utilizing different pathways may enhance the production and release of reactive oxygen species (ROS) and augment the inflammatory cytokine cascade from microglia. These ROS and cytokines may increase the susceptibility of motoneurons to glutamate toxicity and inhibit the function and expression of astrocytic glutamate transporters resulting in further neurotoxicity. Thus, the cumulative evidence suggests that inflammation plays a central role in ALS and manipulating these microglial effector functions may potentially modify the outcome of this devastating disease.


M2 alternatively activated M1 classically activated regulatory Treg 



This study was supported by grants from the Muscular Dystrophy Association and the NIH.


  1. Alexianu ME, Kozovska M, Appel SH (2001) Immune reactivity in a mouse model of familial ALS correlates with disease progression. Neurology 57:1282–1289PubMedGoogle Scholar
  2. Almer G, Vukosavic S, Romero N, Przedborski S (1999) Inducible nitric oxide synthase up-regulation in a transgenic mouse model of familial amyotrophic lateral sclerosis. J Neurochem 72:2415–2425CrossRefPubMedGoogle Scholar
  3. Banerjee R, Mosley RL, Reynolds AD, Dhar A, Jackson-Lewis V, Gordon PH, Przedborski S, Gendelman HE (2008) Adaptive immune neuroprotection in G93A-SOD1 amyotrophic lateral sclerosis mice. PLoS ONE 3:e2740CrossRefPubMedGoogle Scholar
  4. Baron P, Bussini S, Cardin V, Corbo M, Conti G, Galimberti D, Scarpini E, Bresolin N, Wharton SB, Shaw PJ, Silani V (2005) Production of monocyte chemoattractant protein-1 in amyotrophic lateral sclerosis. Muscle Nerve 32:541–544CrossRefPubMedGoogle Scholar
  5. Beers DR, Henkel JS, Xiao Q, Zhao W, Wang J, Yen AA, Siklos L, McKercher SR, Appel SH (2006) Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 103:16021–16026CrossRefPubMedGoogle Scholar
  6. Beers DR, Henkel JS, Zhao W, Wang J, Appel SH (2008) CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc Natl Acad Sci U S A 105:15558–15563CrossRefPubMedGoogle Scholar
  7. Benoit M, Desnues B, Mege JL (2008) Macrophage polarization in bacterial infections. J Immunol 181:3733–3739PubMedGoogle Scholar
  8. Boillée S, Vande Velde C, Cleveland DW (2006a) ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 52:39–59CrossRefPubMedGoogle Scholar
  9. Boillée S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, Kollias G, Cleveland DW (2006b) Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312:1389–1392CrossRefPubMedGoogle Scholar
  10. Borchelt DR, Lee MK, Slunt HS, Guarnieri M, Xu ZS, Wong PC, Brown RH Jr, Price DL, Sisodia SS, Cleveland DW (1994) Superoxide dismutase 1 with mutations linked to familial amyotrophic lateral sclerosis possesses significant activity. Proc Natl Acad Sci U S A 91:8292–8296CrossRefPubMedGoogle Scholar
  11. Bruijn LI, Becher MW, Lee MK, Anderson KL, Jenkins NA, Copeland NG, Sisodia SS, Rothstein JD, Borchelt DR, Price DL, Cleveland DW (1997) ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18:327–338CrossRefPubMedGoogle Scholar
  12. Buechler C, Ritter M, Orsó E, Langmann T, Klucken J, Schmitz G (2000) Regulation of scavenger receptor CD163 expression in human monocytes and macrophages by pro- and antiinflammatory stimuli. J Leukoc Biol 67:97–103PubMedGoogle Scholar
  13. Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9:917–924CrossRefPubMedGoogle Scholar
  14. Carson MJ, Doose JM, Melchior B, Schmid CD, Ploix CC (2006) CNS immune privilege: hiding in plain sight. Immunol Rev 213:48–65CrossRefPubMedGoogle Scholar
  15. Chang SC, Kao MC, Fu MT, Lin CT (2001) Modulation of NO and cytokines in microglial cells by Cu/Zn-superoxide dismutase. Free Radic Biol Med 31:1084–1089CrossRefPubMedGoogle Scholar
  16. Chiu IM, Chen A, Zheng Y, Kosaras B, Tsiftsoglou SA, Vartanian TK, Brown RH Jr, Carroll MC (2008) T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS. Proc Natl Acad Sci U S A 105:17913–17918CrossRefPubMedGoogle Scholar
  17. Clement AM, Nguyen MD, Roberts EA, Garcia ML, Boillée S, Rule M, McMahon AP, Doucette W, Siwek D, Ferrante RJ, Brown RH Jr, Julien JP, Goldstein LS, Cleveland DW (2003) Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302:113–117CrossRefPubMedGoogle Scholar
  18. D’Ercole AJ, Ye P (2008) Expanding the mind: insulin-like growth factor I and brain development. Endocrinology 149:5958–5962CrossRefGoogle Scholar
  19. Dimayuga FO, Wang C, Clark JM, Dimayuga ER, Dimayuga VM, Bruce-Keller AJ (2007) SOD1 overexpression alters ROS production and reduces neurotoxic inflammatory signaling in microglial cells. J Neuroimmunol 182:89–99CrossRefPubMedGoogle Scholar
  20. Ebert S, Schoeberl T, Walczak Y, Stoecker K, Stempfl T, Moehle C, Weber BH, Langmann T (2008) Chondroitin sulfate disaccharide stimulates microglia to adopt a novel regulatory phenotype. J Leukoc Biol 84:736–740CrossRefPubMedGoogle Scholar
  21. Edwards JP, Zhang X, Frauwirth KA, Mosser DM (2006) Biochemical and functional characterization of three activated macrophage populations. J Leukoc Biol 80:1298–1307CrossRefPubMedGoogle Scholar
  22. Elliott JL (2001) Cytokine upregulation in a murine model of familial amyotrophic lateral sclerosis. Brain Res Mol Brain Res 95:172–178CrossRefPubMedGoogle Scholar
  23. Engelhardt JI, Tajti J, Appel SH (1993) Lymphocytic infiltrates in the spinal cord in amyotrophic lateral sclerosis. Arch Neurol 50:30–36PubMedGoogle Scholar
  24. Ezzi SA, Urushitani M, Julien JP (2007) Wild-type superoxide dismutase acquires binding and toxic properties of ALS-linked mutant forms through oxidation. J Neurochem 102:170–178CrossRefPubMedGoogle Scholar
  25. Fendrick SE, Xue QS, Streit WJ (2007) Formation of multinucleated giant cells and microglial degeneration in rats expressing a mutant Cu/Zn superoxide dismutase gene. J Neuroinflammation 4:9CrossRefPubMedGoogle Scholar
  26. Fischer LR, Culver DG, Tennant P, Davis AA, Wang M, Castellano-Sanchez A, Khan J, Polak MA, Glass JD (2004) Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol 185:232–240CrossRefPubMedGoogle Scholar
  27. Geissmann F, Auffray C, Palframan R, Wirrig C, Ciocca A, Campisi L, Narni-Mancinelli E, Lauvau G (2008) Blood monocytes: distinct subsets, how they relate to dendritic cells, and their possible roles in the regulation of T-cell responses. Immunol Cell Biol 86:398–408CrossRefPubMedGoogle Scholar
  28. Gong YH, Parsadanian AS, Andreeva A, Snider WD, Elliott JL (2000) Restricted expression of G86R Cu/Zn superoxide dismutase in astrocytes results in astrocytosis but does not cause motoneuron degeneration. J Neurosci 20:660–665PubMedGoogle Scholar
  29. Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964CrossRefPubMedGoogle Scholar
  30. Gowing G, Philips T, Van Wijmeersch B, Audet JN, Dewil M, Van Den Bosch L, Billiau AD, Robberecht W, Julien JP (2008) Ablation of proliferating microglia does not affect motor neuron degeneration in amyotrophic lateral sclerosis caused by mutant superoxide dismutase. J Neurosci 28:10234–10244CrossRefPubMedGoogle Scholar
  31. Gruzman A, Wood WL, Alpert E, Prasad MD, Miller RG, Rothstein JD, Bowser R, Hamilton R, Wood TD, Cleveland DW, Lingappa VR, Liu J (2007) Common molecular signature in SOD1 for both sporadic and familial amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 104:12524–12529CrossRefPubMedGoogle Scholar
  32. Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX, Chen W, Zhai P, Sufit RL, Siddique T (1994) Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science 264:1772–1775CrossRefPubMedGoogle Scholar
  33. Hall ED, Oostveen JA, Gurney ME (1998) Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia 23:249–256CrossRefPubMedGoogle Scholar
  34. Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394CrossRefPubMedGoogle Scholar
  35. Harraz MM, Marden JJ, Zhou W, Zhang Y, Williams A, Sharov VS, Nelson K, Luo M, Paulson H, Schöneich C, Engelhardt JF (2008) SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model. J Clin Invest 118:659–670PubMedGoogle Scholar
  36. He BP, Wen W, Strong MJ (2002) Activated microglia (BV-2) facilitation of TNF-alpha-mediated motor neuron death in vitro. J Neuroimmunol 128:31–38CrossRefPubMedGoogle Scholar
  37. Henkel JS, Engelhardt JI, Siklós L, Simpson EP, Kim SH, Pan T, Goodman JC, Siddique T, Beers DR, Appel SH (2004) Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann Neurol 55:221–235CrossRefPubMedGoogle Scholar
  38. Henkel JS, Beers DR, Siklós L, Appel SH (2006) The chemokine MCP-1 and the dendritic and myeloid cells it attracts are increased in the mSOD1 mouse model of ALS. Mol Cell Neurosci 31:427–437CrossRefPubMedGoogle Scholar
  39. Hensley K, Floyd RA, Gordon B, Mou S, Pye QN, Stewart C, West M, Williamson K (2002) Temporal patterns of cytokine and apoptosis-related gene expression in spinal cords of the G93A-SOD1 mouse model of amyotrophic lateral sclerosis. J Neurochem 82:365–374 Erratum in: J Neurochem 2002 82:1570CrossRefPubMedGoogle Scholar
  40. Hensley K, Fedynyshyn J, Ferrell S, Floyd RA, Gordon B, Grammas P, Hamdheydari L, Mhatre M, Mou S, Pye QN, Stewart C, West M, West S, Williamson KS (2003) Message and protein-level elevation of tumor necrosis factor alpha (TNF alpha) and TNF alpha-modulating cytokines in spinal cords of the G93A-SOD1 mouse model for amyotrophic lateral sclerosis. Neurobiol Dis 14:74–80CrossRefPubMedGoogle Scholar
  41. Hu S, Sheng WS, Ehrlich LC, Peterson PK, Chao CC (2000) Cytokine effects on glutamate uptake by human astrocytes. Neuroimmunomodulation 7:153–159CrossRefPubMedGoogle Scholar
  42. Howland DS, Liu J, She Y, Goad B, Maragakis NJ, Kim B, Erickson J, Kulik J, DeVito L, Psaltis G, DeGennaro LJ, Cleveland DW, Rothstein JD (2002) Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci U S A 99:1604–1609CrossRefPubMedGoogle Scholar
  43. Ince PG, Shaw PJ, Slade JY, Jones C, Hudgson P (1996) Familial amyotrophic lateral sclerosis with a mutation in exon 4 of the Cu/Zn superoxide dismutase gene: pathological and immunocytochemical changes. Acta Neuropathol 92:395–403CrossRefPubMedGoogle Scholar
  44. Isgaard J, Aberg D, Nilsson M (2007) Protective and regenerative effects of the GH/IGF-I axis on the brain. Minerva Endocrinol 32:103–113PubMedGoogle Scholar
  45. Jaarsma D, Teuling E, Haasdijk ED, De Zeeuw CI, Hoogenraad CC (2008) Neuron-specific expression of mutant superoxide dismutase is sufficient to induce amyotrophic lateral sclerosis in transgenic mice. J Neurosci 28:2075–2088CrossRefPubMedGoogle Scholar
  46. Kang J, Rivest S (2007) MyD88-deficient bone marrow cells accelerate onset and reduce survival in a mouse model of amyotrophic lateral sclerosis. J Cell Biol 179:1219–1230CrossRefPubMedGoogle Scholar
  47. Kassa RM, Mariotti R, Bonaconsa M, Bertini G, Bentivoglio M (2009) Gene, cell, and axon changes in the familial amyotrophic lateral sclerosis mouse sensorimotor cortex. J Neuropathol Exp Neurol 68:59–72CrossRefPubMedGoogle Scholar
  48. Kawamata T, Akiyama H, Yamada T, McGeer PL (1992) Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am J Pathol 140:691–707PubMedGoogle Scholar
  49. Kim SY, Choi SY, Chao W, Volsky DJ (2003) Transcriptional regulation of human excitatory amino acid transporter 1 (EAAT1): cloning of the EAAT1 promoter and characterization of its basal and inducible activity in human astrocytes. J Neurochem 87:1485–1498PubMedCrossRefGoogle Scholar
  50. Komohara Y, Ohnishi K, Kuratsu J, Takeya M (2008) Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J Pathol 216:15–24CrossRefPubMedGoogle Scholar
  51. Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318CrossRefPubMedGoogle Scholar
  52. Kuhle J, Lindberg RL, Regeniter A, Mehling M, Steck AJ, Kappos L, Czaplinski A (2009) Increased levels of inflammatory chemokines in amyotrophic lateral sclerosis. Eur J Neurol 16:771–774CrossRefPubMedGoogle Scholar
  53. Lampson LA, Kushner PD, Sobel RA (1990) Major histocompatibility complex antigen expression in the affected tissues in amyotrophic lateral sclerosis. Ann Neurol 28:365–372CrossRefPubMedGoogle Scholar
  54. Li B, Guo YS, Sun MM, Dong H, Wu SY, Wu DX, Li CY (2008) The NADPH oxidase is involved in lipopolysaccharide-mediated motor neuron injury. Brain Res 1226:199–208CrossRefPubMedGoogle Scholar
  55. Liao SL, Chen CJ (2001) Differential effects of cytokines and redox potential on glutamate uptake in rat cortical glial cultures. Neurosci Lett 299:113–116CrossRefPubMedGoogle Scholar
  56. Lino MM, Schneider C, Caroni P (2002) Accumulation of SOD1 mutants in postnatal motoneurons does not cause motoneuron pathology or motoneuron disease. J Neurosci 22:4825–4832PubMedGoogle Scholar
  57. Lippa CF, Smith TW, Flanders KC (1995) Transforming growth factor-beta: neuronal and glial expression in CNS degenerative diseases. Neurodegeneration 4:425–432CrossRefPubMedGoogle Scholar
  58. Liu Y, Hao W, Dawson A, Liu S, Fassbender K (2009a) Expression of amyotrophic lateral sclerosis-linked SOD1 mutant increases the neurotoxic potential of microglia via TLR2. J Biol Chem 284:3691–3699CrossRefPubMedGoogle Scholar
  59. Liu H-N, Sanelli T, Horne P, Pioro EP, Strong MJ, Rogaeva E, Bilbao J, Zinman L, Robertson J (2009b) Lack of evidence of monomer/misfolded superoxide dismutase-1 in sporadic amyotrophic lateral sclerosis. Ann Neurol 66:75–80CrossRefPubMedGoogle Scholar
  60. Martinez FO, Sica A, Mantovani A, Locati M (2008) Macrophage activation and polarization. Front Biosci 13:453–461CrossRefPubMedGoogle Scholar
  61. Marden JJ, Harraz MM, Williams AJ, Nelson K, Luo M, Paulson H, Engelhardt JF (2007) Redox modifier genes in amyotrophic lateral sclerosis in mice. J Clin Invest 117:2913–2919CrossRefPubMedGoogle Scholar
  62. McGeer PL, Itagaki S, McGeer EG (1988) Expression of the histocompatibility glycoprotein HLA-DR in neurological disease. Acta Neuropathol 76:550–557CrossRefPubMedGoogle Scholar
  63. McKercher SR, Torbett BE, Anderson KL, Henkel GW, Vestal DJ, Baribault H, Klemsz M, Feeney AJ, Wu GE, Paige CJ, Maki RA (1996) Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. EMBO J 15:5647–5658PubMedGoogle Scholar
  64. Michelucci A, Heurtaux T, Grandbarbe L, Morga E, Heuschling P (2009) Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: effects of oligomeric and fibrillar amyloid-beta. J Neuroimmunol 210:3–12CrossRefPubMedGoogle Scholar
  65. Miralles VJ, Martínez-López I, Zaragozá R, Borrás E, García C, Pallardó FV, Viña JR (2001) Na+ dependent glutamate transporters (EAAT1, EAAT2, and EAAT3) in primary astrocyte cultures: effect of oxidative stress. Brain Res 922:21–29CrossRefPubMedGoogle Scholar
  66. Mitchell RM, Freeman WM, Randazzo WT, Stephens HE, Beard JL, Simmons Z, Connor JR (2009) A CSF biomarker panel for identification of patients with amyotrophic lateral sclerosis. Neurology 72:14–149CrossRefPubMedGoogle Scholar
  67. Moisse K, Strong MJ (2006) Innate immunity in amyotrophic lateral sclerosis. Biochim Biophys Acta 1762:1083–1093PubMedGoogle Scholar
  68. Nagata T, Nagano I, Shiote M, Narai H, Murakami T, Hayashi T, Shoji M, Abe K (2007) Elevation of MCP-1 and MCP-1/VEGF ratio in cerebrospinal fluid of amyotrophic lateral sclerosis patients. Neurol Res 29:772–776CrossRefPubMedGoogle Scholar
  69. Nguyen MD, D’Aigle T, Gowing G, Julien JP, Rivest S (2004) Exacerbation of motor neuron disease by chronic stimulation of innate immunity in a mouse model of amyotrophic lateral sclerosis. J Neurosci 24:1340–1349CrossRefPubMedGoogle Scholar
  70. Piani D, Frei K, Pfister HW, Fontana A (1993) Glutamate uptake by astrocytes is inhibited by reactive oxygen intermediates but not by other macrophage-derived molecules including cytokines, leukotrienes or platelet-activating factor. J Neuroimmunol 48:99–104CrossRefPubMedGoogle Scholar
  71. Ponomarev ED, Maresz K, Tan Y, Dittel BN (2007) CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. J Neurosci 27:10714–10721CrossRefPubMedGoogle Scholar
  72. Pramatarova A, Laganière J, Roussel J, Brisebois K, Rouleau GA (2001) Neuron-specific expression of mutant superoxide dismutase 1 in transgenic mice does not lead to motor impairment. J Neurosci 21:3369–3374PubMedGoogle Scholar
  73. Rakhit R, Crow JP, Lepock JR, Kondejewski LH, Cashman NR, Chakrabartty A (2004) Monomeric Cu, Zn-superoxide dismutase is a common misfolding intermediate in the oxidation models of sporadic and familial amyotrophic lateral sclerosis. J Biol Chem 279:15499–15504CrossRefPubMedGoogle Scholar
  74. Rakhit R, Robertson J, Vande Velde C, Horne P, Ruth DM, Griffin J, Cleveland DW, Cashman NR, Chakrabartty A (2007) An immunological epitope selective for pathological monomer-misfolded SOD1 in ALS. Nat Med 13:754–759CrossRefPubMedGoogle Scholar
  75. Ransohoff RM, Perry VH (2009) Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 27:119–145CrossRefPubMedGoogle Scholar
  76. Rentzos M, Nikolaou C, Rombos A, Boufidou F, Zoga M, Dimitrakopoulos A, Tsoutsou A, Vassilopoulos D (2007) RANTES levels are elevated in serum and cerebrospinal fluid in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler 8:283–287PubMedCrossRefGoogle Scholar
  77. Ripps ME, Huntley GW, Hof PR, Morrison JH, Gordon JW (1995) Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 92:689–693CrossRefPubMedGoogle Scholar
  78. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O’Regan JP, Deng HX, Rahmani Z, Krizus A, McKenna-Yasek D, Cayabyab A, Gaston SM, Berger R, Tanzi RE, Halperin JJ, Herzfeldt B, Van den Bergh R, Hung W-Y, Bird T, Deng G, Mulder DW, Smyth C, Laing NG, Soriano E, Pericak-Vance MA, Haines J, Rouleau GA, Gusella JS, Horvitz HR, Brown RH (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62CrossRefPubMedGoogle Scholar
  79. Sitcheran R, Gupta P, Fisher PB, Baldwin AS (2005) Positive and negative regulation of EAAT2 by NF-kappaB: a role for N-myc in TNFalpha-controlled repression. EMBO J 24:510–520CrossRefPubMedGoogle Scholar
  80. Sorg O, Horn TF, Yu N, Gruol DL, Bloom FE (1997) Inhibition of astrocyte glutamate uptake by reactive oxygen species: role of antioxidant enzymes. Mol Med 3:431–440PubMedGoogle Scholar
  81. Tanaka M, Kikuchi H, Ishizu T, Minohara M, Osoegawa M, Motomura K, Tateishi T, Ohyagi Y, Kira J (2006) Intrathecal upregulation of granulocyte colony stimulating factor and its neuroprotective actions on motor neurons in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 65:816–825CrossRefPubMedGoogle Scholar
  82. Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, Taams LS (2007) CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci U S A 104:19446–19451CrossRefPubMedGoogle Scholar
  83. Town T, Nikolic V, Tan J (2005) The microglial “activation” continuum: from innate to adaptive responses. J Neuroinflammation 2:24CrossRefPubMedGoogle Scholar
  84. Troost D, van den Oord JJ, de Jong JM, Swaab DF (1989) Lymphocytic infiltration in the spinal cord of patients with amyotrophic lateral sclerosis. Clin Neuropathol 8:289–294PubMedGoogle Scholar
  85. Troost D, Van den Oord JJ, Vianney de Jong JM (1990) Immunohistochemical characterization of the inflammatory infiltrate in amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol 16:401–410CrossRefPubMedGoogle Scholar
  86. Trotti D, Rossi D, Gjesdal O, Levy LM, Racagni G, Danbolt NC, Volterra A (1996) Peroxynitrite inhibits glutamate transporter subtypes. J Biol Chem 271:5976–5979CrossRefPubMedGoogle Scholar
  87. Turner MR, Cagnin A, Turkheimer FE, Miller CC, Shaw CE, Brooks DJ, Leigh PN, Banati RB (2004) Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis 15:601–609CrossRefPubMedGoogle Scholar
  88. Urushitani M, Sik A, Sakurai T, Nukina N, Takahashi R, Julien JP (2006) Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis. Nat Neurosci 9:108–118CrossRefPubMedGoogle Scholar
  89. Urushitani M, Ezzi SA, Matsuo A, Tooyama I, Julien JP (2008) The endoplasmic reticulum–Golgi pathway is a target for translocation and aggregation of mutant superoxide dismutase linked to ALS. FASEB J 22:2476–2487CrossRefPubMedGoogle Scholar
  90. Weydt P, Yuen EC, Ransom BR, Möller T (2004) Increased cytotoxic potential of microglia from ALS-transgenic mice. Glia 48:179–182CrossRefPubMedGoogle Scholar
  91. Wilms H, Sievers J, Dengler R, Bufler J, Deuschl G, Lucius R (2003) Intrathecal synthesis of monocyte chemoattractant protein-1 (MCP-1) in amyotrophic lateral sclerosis: further evidence for microglial activation in neurodegeneration. J Neuroimmunol 144:139–142CrossRefPubMedGoogle Scholar
  92. Wong PC, Pardo CA, Borchelt DR, Lee MK, Copeland NG, Jenkins NA, Sisodia SS, Cleveland DW, Price DL (1995) An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14:1105–1116CrossRefPubMedGoogle Scholar
  93. Wu DC, Ré DB, Nagai M, Ischiropoulos H, Przedborski S (2006) The inflammatory NADPH oxidase enzyme modulates motor neuron degeneration in amyotrophic lateral sclerosis mice. Proc Natl Acad Sci U S A 103:12132–12137CrossRefPubMedGoogle Scholar
  94. Xiao Q, Zhao W, Beers DR, Yen AA, Xie W, Henkel JS, Appel SH (2007) Mutant SOD1(G93A) microglia are more neurotoxic relative to wild-type microglia. J Neurochem 102:2008–2019CrossRefPubMedGoogle Scholar
  95. Xie Y, Weydt P, Howland DS, Kliot M, Möller T (2004) Inflammatory mediators and growth factors in the spinal cord of G93A SOD1 rats. NeuroReport 15:2513–2516CrossRefPubMedGoogle Scholar
  96. Yamanaka K, Boillée S, Roberts EA, Garcia ML, McAlonis-Downes M, Mikse OR, Cleveland DW, Goldstein LS (2008a) Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice. Proc Natl Acad Sci U S A 105:7594–7599CrossRefPubMedGoogle Scholar
  97. Yamanaka K, Chun SJ, Boillée S, Fujimori-Tonou N, Yamashita H, Gutmann DH, Takahashi R, Misawa H, Cleveland DW (2008b) Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci 11:251–253CrossRefPubMedGoogle Scholar
  98. Yoshihara T, Ishigaki S, Yamamoto M, Liang Y, Niwa J, Takeuchi H, Doyu M, Sobue G (2002) Differential expression of inflammation- and apoptosis-related genes in spinal cords of a mutant SOD1 transgenic mouse model of familial amyotrophic lateral sclerosis. J Neurochem 80:158–167CrossRefPubMedGoogle Scholar
  99. Zhao W, Xie W, Le W, Beers DR, He Y, Henkel JS, Simpson EP, Yen AA, Xiao Q, Appel SH (2004) Activated microglia initiate motor neuron injury by a nitric oxide and glutamate-mediated mechanism. J Neuropathol Exp Neurol 63:964–977PubMedGoogle Scholar
  100. Zhao W, Xie W, Xiao Q, Beers DR, Appel SH (2006) Protective effects of an anti-inflammatory cytokine, interleukin-4, on motoneuron toxicity induced by activated microglia. J Neurochem 99:1176–1187CrossRefPubMedGoogle Scholar
  101. Zhao W, Beers DR, Henkel JS, Zhang W, Urushitani M, Julien J-P, Appel SH (2009) Extracellular mutant SOD1 induces microglial-mediated motoneuron injury. Glia (in press)Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Jenny S. Henkel
    • 1
  • David R. Beers
    • 1
  • Weihua Zhao
    • 1
  • Stanley H. Appel
    • 1
  1. 1.Department of Neurology, Methodist Neurological Institute, The Methodist Hospital Research InstituteThe Methodist HospitalHoustonUSA

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