1932

Abstract

Astrocytes undergo important phenotypic changes in many neurological disorders, including strokes, trauma, inflammatory diseases, infectious diseases, and neurodegenerative diseases. We have been studying the astrocytes of Alexander disease (AxD), which is caused by heterozygous mutations in the gene, which is the gene that encodes the major astrocyte intermediate filament protein. AxD is a primary astrocyte disease because expression is specific to astrocytes in the central nervous system (CNS). The accumulation of extremely large amounts of GFAP causes many molecular changes in astrocytes, including proteasome inhibition, stress kinase activation, mechanistic target of rapamycin (mTOR) activation, loss of glutamate and potassium buffering capacity, loss of astrocyte coupling, and changes in cell morphology. Many of these changes appear to be common to astrocyte reactions in other neurological disorders. Using AxD to illuminate common mechanisms, we discuss the molecular pathology of AxD astrocytes and compare that to astrocyte pathology in other disorders.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pathol-052016-100218
2017-01-24
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/pathol/12/1/annurev-pathol-052016-100218.html?itemId=/content/journals/10.1146/annurev-pathol-052016-100218&mimeType=html&fmt=ahah

Literature Cited

  1. Messing A, Brenner M, Feany MB, Nedergaard M, Goldman JE. 1.  2012. Alexander disease. J. Neurosci. 32:5017–23 [Google Scholar]
  2. Prust M, Wang J, Morizono H, Messing A, Brenner M. 2.  et al. 2011. GFAP mutations, age at onset, and clinical subtypes in Alexander disease. Neurology 77:1287–94 [Google Scholar]
  3. Iwaki T, Iwaki A, Tateishi J, Sakaki Y, Goldman JE. 3.  1993. αB-crystallin and 27-kd heat shock protein are regulated by stress conditions in the central nervous system and accumulate in Rosenthal fibers. Am. J. Pathol. 143:487–95 [Google Scholar]
  4. Wohlwill FJ, Bernstein J, Yakovlev PI. 4.  1959. Dysmyelinogenic leukodystrophy; report of a case of a new, presumably familial type of leukodystrophy with megalobarencephaly. J. Neuropathol. Exp. Neurol. 18:359–83 [Google Scholar]
  5. Russo LS Jr., Aron A, Anderson PJ. 5.  1976. Alexander's disease: a report and reappraisal. Neurology 26:607–14 [Google Scholar]
  6. Hagemann TL, Gaeta SA, Smith MA, Johnson DA, Johnson JA, Messing A. 6.  2005. Gene expression analysis in mice with elevated glial fibrillary acidic protein and Rosenthal fibers reveals a stress response followed by glial activation and neuronal dysfunction. Hum. Mol. Genet. 14:2443–58 [Google Scholar]
  7. Jany PL, Hagemann TL, Messing A. 7.  2013. GFAP expression as an indicator of disease severity in mouse models of Alexander disease. ASN Neuro 5:e00109 [Google Scholar]
  8. Tang G, Perng MD, Wilk S, Quinlan R, Goldman JE. 8.  2010. Oligomers of mutant glial fibrillary acidic protein (GFAP) inhibit the proteasome system in Alexander disease astrocytes, and the small heat shock protein αB-crystallin reverses the inhibition. J. Biol. Chem. 285:10527–37 [Google Scholar]
  9. Tang G, Xu Z, Goldman JE. 9.  2006. Synergistic effects of the SAPK/JNK and the proteasome pathway on glial fibrillary acidic protein (GFAP) accumulation in Alexander disease. J. Biol. Chem. 281:38634–43 [Google Scholar]
  10. Tang G, Yue Z, Talloczy Z, Hagemann T, Cho W. 10.  et al. 2008. Autophagy induced by Alexander disease-mutant GFAP accumulation is regulated by p38/MAPK and mTOR signaling pathways. Hum. Mol. Genet. 17:1540–55 [Google Scholar]
  11. Sosunov AA, Guilfoyle E, Wu X, McKhann GM 2nd, Goldman JE. 11.  2013. Phenotypic conversions of “protoplasmic” to “reactive” astrocytes in Alexander disease. J. Neurosci. 33:7439–50 [Google Scholar]
  12. Tang G, Yue Z, Talloczy Z, Goldman JE. 12.  2008. Adaptive autophagy in Alexander disease–affected astrocytes. Autophagy 4:701–3 [Google Scholar]
  13. Tang G, Gudsnuk K, Kuo SH, Cotrina ML, Rosoklija G. 13.  et al. 2014. Loss of mTOR-dependent macro-autophagy causes autistic-like synaptic pruning deficits. Neuron 83:1131–43 [Google Scholar]
  14. Tian R, Wu X, Hagemann TL, Sosunov AA, Messing A. 14.  et al. 2010. Alexander disease mutant glial fibrillary acidic protein compromises glutamate transport in astrocytes. J. Neuropathol. Exp. Neurol. 69:335–45 [Google Scholar]
  15. Olabarria M, Putilina M, Riemer EC, Goldman JE. 15.  2015. Astrocyte pathology in Alexander disease causes a marked inflammatory environment. Acta Neuropathol 130:469–86 [Google Scholar]
  16. Yamamoto T, Ochalski A, Hertzberg EL, Nagy JI. 16.  1990. LM and EM immunolocalization of the gap junctional protein connexin 43 in rat brain. Brain Res 508:313–19 [Google Scholar]
  17. Nagy JI, Ochalski PA, Li J, Hertzberg EL. 17.  1997. Evidence for the co-localization of another connexin with connexin-43 at astrocytic gap junctions in rat brain. Neuroscience 78:533–48 [Google Scholar]
  18. Nagy JI, Patel D, Ochalski PA, Stelmack GL. 18.  1999. Connexin30 in rodent, cat and human brain: selective expression in gray matter astrocytes, co-localization with connexin43 at gap junctions and late developmental appearance. Neuroscience 88:447–68 [Google Scholar]
  19. Lutz SE, Zhao Y, Gulinello M, Lee SC, Raine CS, Brosnan CF. 19.  2009. Deletion of astrocyte connexins 43 and 30 leads to a dysmyelinating phenotype and hippocampal CA1 vacuolation. J. Neurosci. 29:7743–52 [Google Scholar]
  20. Bushong EA, Martone ME, Jones YZ, Ellisman MH. 20.  2002. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J. Neurosci. 22:183–92 [Google Scholar]
  21. Aruffo A, Stamenkovic I, Melnick M, Underhill CB, Seed B. 21.  1990. CD44 is the principal cell surface receptor for hyaluronate. Cell 61:1303–13 [Google Scholar]
  22. Naor D, Sionov RV, Ish-Shalom D. 22.  1997. CD44: structure, function, and association with the malignant process. Adv. Cancer Res. 71:241–319 [Google Scholar]
  23. Sosunov AA, Wu X, Tsankova NM, Guilfoyle E, McKhann GM 2nd, Goldman JE. 23.  2014. Phenotypic heterogeneity and plasticity of isocortical and hippocampal astrocytes in the human brain. J. Neurosci. 34:2285–98 [Google Scholar]
  24. Thompson WL, Van Eldik LJ. 24.  2009. Inflammatory cytokines stimulate the chemokines CCL2/MCP-1 and CCL7/MCP-3 through NFkB and MAPK dependent pathways in rat astrocytes [corrected]. Brain Res128747–57
  25. Majumder S, Zhou LZ, Chaturvedi P, Babcock G, Aras S, Ransohoff RM. 25.  1998. p48/STAT-1α-containing complexes play a predominant role in induction of IFN-γ-inducible protein, 10 kDa (IP-10) by IFN-γ alone or in synergy with TNF-α. J. Immunol. 161:4736–44 [Google Scholar]
  26. Goetz DH, Holmes MA, Borregaard N, Bluhm ME, Raymond KN, Strong RK. 26.  2002. The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol. Cell 10:1033–43 [Google Scholar]
  27. Bao G, Clifton M, Hoette TM, Mori K, Deng SX. 27.  et al. 2010. Iron traffics in circulation bound to a siderocalin (Ngal)-catechol complex. Nat. Chem. Biol. 6:602–9 [Google Scholar]
  28. Devireddy LR, Hart DO, Goetz DH, Green MR. 28.  2010. A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production. Cell 141:1006–17 [Google Scholar]
  29. Ferreira AC, Da Mesquita S, Sousa JC, Correia-Neves M, Sousa N. 29.  et al. 2015. From the periphery to the brain: lipocalin-2, a friend or foe?. Prog. Neurobiol. 131:120–36 [Google Scholar]
  30. Jeon S, Jha MK, Ock J, Seo J, Jin M. 30.  et al. 2013. Role of lipocalin-2-chemokine axis in the development of neuropathic pain following peripheral nerve injury. J. Biol. Chem. 288:24116–27 [Google Scholar]
  31. Lee S, Kim JH, Kim JH, Seo JW, Han HS. 31.  et al. 2011. Lipocalin-2 is a chemokine inducer in the central nervous system: role of chemokine ligand 10 (CXCL10) in lipocalin-2-induced cell migration. J. Biol. Chem. 286:43855–70 [Google Scholar]
  32. Biber K, Dijkstra I, Trebst C, De Groot CJ, Ransohoff RM, Boddeke HW. 32.  2002. Functional expression of CXCR3 in cultured mouse and human astrocytes and microglia. Neuroscience 112:487–97 [Google Scholar]
  33. Clarner T, Janssen K, Nellessen L, Stangel M, Skripuletz T. 33.  et al. 2015. CXCL10 triggers early microglial activation in the cuprizone model. J. Immunol. 194:3400–13 [Google Scholar]
  34. Rappert A, Bechmann I, Pivneva T, Mahlo J, Biber K. 34.  et al. 2004. CXCR3-dependent microglial recruitment is essential for dendrite loss after brain lesion. J. Neurosci. 24:8500–9 [Google Scholar]
  35. Singhal G, Jaehne EJ, Corrigan F, Toben C, Baune BT. 35.  2014. Inflammasomes in neuroinflammation and changes in brain function: a focused review. Front. Neurosci. 8:315 [Google Scholar]
  36. Iwaki T, Kume-Iwaki A, Liem RK, Goldman JE. 36.  1989. αB-crystallin is expressed in non-lenticular tissues and accumulates in Alexander's disease brain. Cell 57:71–78 [Google Scholar]
  37. Che X, Ye W, Panga L, Wu DC, Yang GY. 37.  2001. Monocyte chemoattractant protein-1 expressed in neurons and astrocytes during focal ischemia in mice. Brain Res 902:171–77 [Google Scholar]
  38. Cheng W, Zhao Q, Xi Y, Li C, Xu Y. 38.  et al. 2015. IFN-β inhibits T cells accumulation in the central nervous system by reducing the expression and activity of chemokines in experimental autoimmune encephalomyelitis. Mol. Immunol. 64:152–62 [Google Scholar]
  39. dos Santos AC, Barsante MM, Arantes RM, Bernard CC, Teixeira MM, Carvalho-Tavares J. 39.  2005. CCL2 and CCL5 mediate leukocyte adhesion in experimental autoimmune encephalomyelitis—an intravital microscopy study. J. Neuroimmunol. 162:122–29 [Google Scholar]
  40. Dos Santos AC, Roffe E, Arantes RM, Juliano L, Pesquero JL. 40.  et al. 2008. Kinin B2 receptor regulates chemokines CCL2 and CCL5 expression and modulates leukocyte recruitment and pathology in experimental autoimmune encephalomyelitis (EAE) in mice. J. Neuroinflamm. 5:49 [Google Scholar]
  41. Jiang L, Newman M, Saporta S, Chen N, Sanberg C. 41.  et al. 2008. MIP-1α and MCP-1 induce migration of human umbilical cord blood cells in models of stroke. Curr. Neurovasc. Res. 5:118–24 [Google Scholar]
  42. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. 42.  2011. Physiology of microglia. Physiol. Rev. 91:461–553 [Google Scholar]
  43. Iwasaki Y, Saito Y, Mori K, Ito M, Mimuro M. 43.  et al. 2015. An autopsied case of adult-onset bulbospinalform Alexander disease with a novel S393R mutation in the GFAP gene. Clin. Neuropathol. 34:207–14 [Google Scholar]
  44. Klein EA, Anzil AP. 44.  1994. Prominent white matter cavitation in an infant with Alexander's disease. Clin. Neuropathol. 13:31–38 [Google Scholar]
  45. Carter SL, Muller M, Manders PM, Campbell IL. 45.  2007. Induction of the genes for Cxcl9 and Cxcl10 is dependent on IFN-γ but shows differential cellular expression in experimental autoimmune encephalomyelitis and by astrocytes and microglia in vitro. Glia 55:1728–39 [Google Scholar]
  46. Omari KM, John GR, Sealfon SC, Raine CS. 46.  2005. CXC chemokine receptors on human oligodendrocytes: implications for multiple sclerosis. Brain 128:1003–15 [Google Scholar]
  47. Sorensen TL, Trebst C, Kivisakk P, Klaege KL, Majmudar A. 47.  et al. 2002. Multiple sclerosis: a study of CXCL10 and CXCR3 co-localization in the inflamed central nervous system. J. Neuroimmunol. 127:59–68 [Google Scholar]
  48. Klein RS. 48.  2004. Regulation of neuroinflammation: the role of CXCL10 in lymphocyte infiltration during autoimmune encephalomyelitis. J. Cell. Biochem. 92:213–22 [Google Scholar]
  49. Klein RS, Izikson L, Means T, Gibson HD, Lin E. 49.  et al. 2004. IFN-inducible protein 10/CXC chemokine ligand 10-independent induction of experimental autoimmune encephalomyelitis. J. Immunol. 172:550–59 [Google Scholar]
  50. Mills Ko E, Ma JH, Guo F, Miers L, Lee E. 50.  et al. 2014. Deletion of astroglial CXCL10 delays clinical onset but does not affect progressive axon loss in a murine autoimmune multiple sclerosis model. J. Neuroinflamm. 11:105 [Google Scholar]
  51. Muller M, Carter SL, Hofer MJ, Manders P, Getts DR. 51.  et al. 2007. CXCR3 signaling reduces the severity of experimental autoimmune encephalomyelitis by controlling the parenchymal distribution of effector and regulatory T cells in the central nervous system. J. Immunol. 179:2774–86 [Google Scholar]
  52. Nash B, Thomson CE, Linington C, Arthur AT, McClure JD. 52.  et al. 2011. Functional duality of astrocytes in myelination. J. Neurosci. 31:13028–38 [Google Scholar]
  53. Back SA, Tuohy TM, Chen H, Wallingford N, Craig A. 53.  et al. 2005. Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation. Nat. Med. 11:966–72 [Google Scholar]
  54. Bugiani M, Postma N, Polder E, Dieleman N, Scheffer PG. 54.  et al. 2013. Hyaluronan accumulation and arrested oligodendrocyte progenitor maturation in vanishing white matter disease. Brain 136:209–22 [Google Scholar]
  55. Back SA, Riddle A, Dean J, Hohimer AR. 55.  2012. The instrumented fetal sheep as a model of cerebral white matter injury in the premature infant. Neurotherapeutics 9:359–70 [Google Scholar]
  56. Rodriguez D, Gauthier F, Bertini E, Bugiani M, Brenner M. 56.  et al. 2001. Infantile Alexander disease: spectrum of GFAP mutations and genotype-phenotype correlation. Am. J. Hum. Genet. 69:1134–40 [Google Scholar]
  57. Cho J, Nelson TE, Bajova H, Gruol DL. 57.  2009. Chronic CXCL10 alters neuronal properties in rat hippocampal culture. J. Neuroimmunol. 207:92–100 [Google Scholar]
  58. Smith JA, Das A, Ray SK, Banik NL. 58.  2012. Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res. Bull. 87:10–20 [Google Scholar]
  59. Vezzani A, Viviani B. 59.  2015. Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. Neuropharmacology 96:70–82 [Google Scholar]
  60. Zhou Y, Tang H, Liu J, Dong J, Xiong H. 60.  2011. Chemokine CCL2 modulation of neuronal excitability and synaptic transmission in rat hippocampal slices. J. Neurochem. 116:406–14 [Google Scholar]
  61. Gosselin RD, Varela C, Banisadr G, Mechighel P, Rostene W. 61.  et al. 2005. Constitutive expression of CCR2 chemokine receptor and inhibition by MCP-1/CCL2 of GABA-induced currents in spinal cord neurones. J. Neurochem. 95:1023–34 [Google Scholar]
  62. Nelson TE, Gruol DL. 62.  2004. The chemokine CXCL10 modulates excitatory activity and intracellular calcium signaling in cultured hippocampal neurons. J. Neuroimmunol. 156:74–87 [Google Scholar]
  63. Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS. 63.  et al. 2007. The classical complement cascade mediates CNS synapse elimination. Cell 131:1164–78 [Google Scholar]
  64. Anderson MA, Ao Y, Sofroniew MV. 64.  2014. Heterogeneity of reactive astrocytes. Neurosci. Lett. 565:23–29 [Google Scholar]
  65. Sofroniew MV, Vinters HV. 65.  2010. Astrocytes: biology and pathology. Acta Neuropathol 119:7–35 [Google Scholar]
  66. Eng LF, Ghirnikar RS, Lee YL. 66.  2000. Glial fibrillary acidic protein: GFAP-thirty-one years (1969–2000). Neurochem. Res. 25:1439–51 [Google Scholar]
  67. Middeldorp J, Hol EM. 67.  2011. GFAP in health and disease. Prog. Neurobiol. 93:421–43 [Google Scholar]
  68. Olabarria M, Noristani HN, Verkhratsky A, Rodriguez JJ. 68.  2010. Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer's disease. Glia 58:831–38 [Google Scholar]
  69. Le Prince G, Delaere P, Fages C, Duyckaerts C, Hauw JJ, Tardy M. 69.  1993. Alterations of glial fibrillary acidic protein mRNA level in the aging brain and in senile dementia of the Alzheimer type. Neurosci. Lett. 151:71–73 [Google Scholar]
  70. Kasai H, Hirano A, Llena JF, Kawamoto K. 70.  1997. A histopathological study of craniopharyngioma with special reference to its stroma and surrounding tissue. Brain Tumor Pathol. 14:41–45 [Google Scholar]
  71. Klein P, Rubinstein LJ. 71.  1989. Benign symptomatic glial cysts of the pineal gland: a report of seven cases and review of the literature. J. Neurol. Neurosurg. Psychiatry 52:991–95 [Google Scholar]
  72. Rosenthal W. 72.  1898. Über eine eigenthümliche, mit Syringomyelie complicirte Geschwulst des Rückenmarks. Bietr. Pathol. Anat. 23:111–43 [Google Scholar]
  73. Herndon RM, Rubinstein LJ, Freeman JM, Mathieson G. 73.  1970. Light and electron microscopic observations on Rosenthal fibers in Alexander's disease and in multiple sclerosis. J. Neuropathol. Exp. Neurol. 29:524–51 [Google Scholar]
  74. Koyama Y, Goldman JE. 74.  1999. Formation of GFAP cytoplasmic inclusions in astrocytes and their disaggregation by αB-crystallin. Am. J. Pathol. 154:1563–72 [Google Scholar]
  75. Kamphuis W, Middeldorp J, Kooijman L, Sluijs JA, Kooi EJ. 75.  et al. 2014. Glial fibrillary acidic protein isoform expression in plaque related astrogliosis in Alzheimer's disease. Neurobiol. Aging 35:492–510 [Google Scholar]
  76. Nishie M, Mori F, Ogawa M, Sannohe S, Tanno K. 76.  et al. 2004. Multinucleated astrocytes in old demyelinated plaques in a patient with multiple sclerosis. Neuropathology 24:248–53 [Google Scholar]
  77. Yokoyama T, Goto H, Izawa I, Mizutani H, Inagaki M. 77.  2005. Aurora-B and Rho-kinase/ROCK, the two cleavage furrow kinases, independently regulate the progression of cytokinesis: possible existence of a novel cleavage furrow kinase phosphorylates ezrin/radixin/moesin (ERM). Genes Cells 10:127–37 [Google Scholar]
  78. Sosunov AA, Wu X, McGovern RA, Coughlin DG, Mikell CB. 78.  et al. 2012. The mTOR pathway is activated in glial cells in mesial temporal sclerosis. Epilepsia 53:Suppl. 178–86 [Google Scholar]
  79. Macias M, Blazejczyk M, Kazmierska P, Caban B, Skalecka A. 79.  et al. 2013. Spatiotemporal characterization of mTOR kinase activity following kainic acid induced status epilepticus and analysis of rat brain response to chronic rapamycin treatment. PLOS ONE 8:e64455 [Google Scholar]
  80. Wang X, Sha L, Sun N, Shen Y, Xu Q. 80.  2016. Deletion of mTOR in reactive astrocytes suppresses chronic seizures in a mouse model of temporal lobe epilepsy. Mol. Neurobiol. In press. doi: 10.1007/s12035-015-9590-7
  81. Codeluppi S, Svensson CI, Hefferan MP, Valencia F, Silldorff MD. 81.  et al. 2009. The Rheb-mTOR pathway is upregulated in reactive astrocytes of the injured spinal cord. J. Neurosci. 29:1093–104 [Google Scholar]
  82. Bordey A, Lyons SA, Hablitz JJ, Sontheimer H. 82.  2001. Electrophysiological characteristics of reactive astrocytes in experimental cortical dysplasia. J. Neurophysiol. 85:1719–31 [Google Scholar]
  83. Faustmann PM, Haase CG, Romberg S, Hinkerohe D, Szlachta D. 83.  et al. 2003. Microglia activation influences dye coupling and Cx43 expression of the astrocytic network. Glia 42:101–8 [Google Scholar]
  84. Aronica E, Gorter JA, Jansen GH, Leenstra S, Yankaya B, Troost D. 84.  2001. Expression of connexin 43 and connexin 32 gap-junction proteins in epilepsy-associated brain tumors and in the perilesional epileptic cortex. Acta Neuropathol 101:449–59 [Google Scholar]
  85. Soroceanu L, Manning TJ Jr., Sontheimer H. 85.  2001. Reduced expression of connexin-43 and functional gap junction coupling in human gliomas. Glia 33:107–17 [Google Scholar]
  86. Loring JF, Wen X, Lee JM, Seilhamer J, Somogyi R. 86.  2001. A gene expression profile of Alzheimer's disease. DNA Cell Biol 20:683–95 [Google Scholar]
  87. Nagy JI, Li W, Hertzberg EL, Marotta CA. 87.  1996. Elevated connexin43 immunoreactivity at sites of amyloid plaques in Alzheimer's disease. Brain Res 717:173–78 [Google Scholar]
  88. Vis JC, Nicholson LF, Faull RL, Evans WH, Severs NJ, Green CR. 88.  1998. Connexin expression in Huntington's diseased human brain. Cell Biol. Int. 22:837–47 [Google Scholar]
  89. Masaki K. 89.  2015. Early disruption of glial communication via connexin gap junction in multiple sclerosis, Balo's disease and neuromyelitis optica. Neuropathology 35:469–80 [Google Scholar]
  90. Masaki K, Suzuki SO, Matsushita T, Yonekawa T, Matsuoka T. 90.  et al. 2012. Extensive loss of connexins in Balo's disease: evidence for an auto-antibody-independent astrocytopathy via impaired astrocyte-oligodendrocyte/myelin interaction. Acta Neuropathol 123:887–900 [Google Scholar]
  91. Schroder W, Hinterkeuser S, Seifert G, Schramm J, Jabs R. 91.  et al. 2000. Functional and molecular properties of human astrocytes in acute hippocampal slices obtained from patients with temporal lobe epilepsy. Epilepsia 41:Suppl. 6S181–84 [Google Scholar]
  92. Sheldon AL, Robinson MB. 92.  2007. The role of glutamate transporters in neurodegenerative diseases and potential opportunities for intervention. Neurochem. Int. 51:333–55 [Google Scholar]
  93. Takahashi K, Foster JB, Lin CL. 93.  2015. Glutamate transporter EAAT2: regulation, function, and potential as a therapeutic target for neurological and psychiatric disease. Cell. Mol. Life Sci. 72:3489–506 [Google Scholar]
  94. Karki P, Webb A, Smith K, Lee K, Son DS. 94.  et al. 2013. cAMP response element-binding protein (CREB) and nuclear factor κB mediate the tamoxifen-induced up-regulation of glutamate transporter 1 (GLT-1) in rat astrocytes. J. Biol. Chem. 288:28975–86 [Google Scholar]
  95. Sitcheran R, Gupta P, Fisher PB, Baldwin AS. 95.  2005. Positive and negative regulation of EAAT2 by NF-κB: a role for N-myc in TNF-α-controlled repression. EMBO J 24:510–20 [Google Scholar]
  96. Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH. 96.  et al. 2005. β-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433:73–77 [Google Scholar]
  97. Lee SG, Su ZZ, Emdad L, Gupta P, Sarkar D. 97.  et al. 2008. Mechanism of ceftriaxone induction of excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes. J. Biol. Chem. 283:13116–23 [Google Scholar]
  98. Jelenkovic AV, Jovanovic MD, Stanimirovic DD, Bokonjic DD, Ocic GG, Boskovic BS. 98.  2008. Beneficial effects of ceftriaxone against pentylenetetrazole-evoked convulsions. Exp. Biol. Med. 233:1389–94 [Google Scholar]
  99. Zeng LH, Bero AW, Zhang B, Holtzman DM, Wong M. 99.  2010. Modulation of astrocyte glutamate transporters decreases seizures in a mouse model of Tuberous Sclerosis Complex. Neurobiol. Dis. 37:764–71 [Google Scholar]
  100. Goodrich GS, Kabakov AY, Hameed MQ, Dhamne SC, Rosenberg PA, Rotenberg A. 100.  2013. Ceftriaxone treatment after traumatic brain injury restores expression of the glutamate transporter, GLT-1, reduces regional gliosis, and reduces post-traumatic seizures in the rat. J. Neurotrauma 30:1434–41 [Google Scholar]
  101. Tong X, Ao Y, Faas GC, Nwaobi SE, Xu J. 101.  et al. 2014. Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington's disease model mice. Nat. Neurosci. 17:694–703 [Google Scholar]
  102. Hagel C, Stavrou DK. 102.  1999. CD44 expression in primary and recurrent oligodendrogliomas and in adjacent gliotic brain tissue. Neuropathol. Appl. Neurobiol. 25:313–18 [Google Scholar]
  103. Pietras A, Katz AM, Ekstrom EJ, Wee B, Halliday JJ. 103.  et al. 2014. Osteopontin-CD44 signaling in the glioma perivascular niche enhances cancer stem cell phenotypes and promotes aggressive tumor growth. Cell Stem Cell 14:357–69 [Google Scholar]
  104. Lee TS, Mane S, Eid T, Zhao H, Lin A. 104.  et al. 2007. Gene expression in temporal lobe epilepsy is consistent with increased release of glutamate by astrocytes. Mol. Med. 13:1–13 [Google Scholar]
  105. Sosunov AA, Wu X, Weiner HL, Mikell CB, Goodman RR. 105.  et al. 2008. Tuberous sclerosis: a primary pathology of astrocytes?. Epilepsia 49:Suppl. 253–62 [Google Scholar]
  106. Mansour H, Asher R, Dahl D, Labkovsky B, Perides G, Bignami A. 106.  1990. Permissive and non-permissive reactive astrocytes: immunofluorescence study with antibodies to the glial hyaluronate-binding protein. J. Neurosci. Res. 25:300–11 [Google Scholar]
  107. Ferrer I, Lopez-Gonzalez I, Carmona M, Arregui L, Dalfo E. 107.  et al. 2014. Glial and neuronal tau pathology in tauopathies: characterization of disease-specific phenotypes and tau pathology progression. J. Neuropathol. Exp. Neurol. 73:81–97 [Google Scholar]
  108. Cui W, Ke JZ, Zhang Q, Ke HZ, Chalouni C, Vignery A. 108.  2006. The intracellular domain of CD44 promotes the fusion of macrophages. Blood 107:796–805 [Google Scholar]
  109. Cho Y, Lee HW, Kang HG, Kim HY, Kim SJ, Chun KH. 109.  2015. Cleaved CD44 intracellular domain supports activation of stemness factors and promotes tumorigenesis of breast cancer. Oncotarget 6:8709–21 [Google Scholar]
  110. Muller M, Carter S, Hofer MJ, Campbell IL. 110.  2010. Review: the chemokine receptor CXCR3 and its ligands CXCL9, CXCL10 and CXCL11 in neuroimmunity—a tale of conflict and conundrum. Neuropathol. Appl. Neurobiol. 36:368–87 [Google Scholar]
  111. Phares TW, Stohlman SA, Hinton DR, Bergmann CC. 111.  2013. Astrocyte-derived CXCL10 drives accumulation of antibody-secreting cells in the central nervous system during viral encephalomyelitis. J. Virol. 87:3382–92 [Google Scholar]
  112. Cole KE, Strick CA, Paradis TJ, Ogborne KT, Loetscher M. 112.  et al. 1998. Interferon-inducible T cell alpha chemoattractant (I-TAC): a novel non-ELR CXC chemokine with potent activity on activated T cells through selective high affinity binding to CXCR3. J. Exp. Med. 187:2009–21 [Google Scholar]
  113. Loetscher M, Gerber B, Loetscher P, Jones SA, Piali L. 113.  et al. 1996. Chemokine receptor specific for IP10 and mig: structure, function, and expression in activated T-lymphocytes. J. Exp. Med. 184:963–69 [Google Scholar]
  114. Gorina R, Font-Nieves M, Marquez-Kisinousky L, Santalucia T, Planas AM. 114.  2011. Astrocyte TLR4 activation induces a proinflammatory environment through the interplay between MyD88-dependent NFκB signaling, MAPK, and Jak1/Stat1 pathways. Glia 59:242–55 [Google Scholar]
  115. Ponath G, Schettler C, Kaestner F, Voigt B, Wentker D. 115.  et al. 2007. Autocrine S100B effects on astrocytes are mediated via RAGE. J. Neuroimmunol. 184:214–22 [Google Scholar]
  116. Brambilla R, Bracchi-Ricard V, Hu WH, Frydel B, Bramwell A. 116.  et al. 2005. Inhibition of astroglial nuclear factor κB reduces inflammation and improves functional recovery after spinal cord injury. J. Exp. Med. 202:145–56 [Google Scholar]
  117. Brambilla R, Persaud T, Hu X, Karmally S, Shestopalov VI. 117.  et al. 2009. Transgenic inhibition of astroglial NF-κB improves functional outcome in experimental autoimmune encephalomyelitis by suppressing chronic central nervous system inflammation. J. Immunol. 182:2628–40 [Google Scholar]
/content/journals/10.1146/annurev-pathol-052016-100218
Loading
/content/journals/10.1146/annurev-pathol-052016-100218
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error