Advertisement

Molecular Neurobiology

, Volume 54, Issue 10, pp 7567–7584 | Cite as

Role of Microglia in Neurological Disorders and Their Potentials as a Therapeutic Target

  • Li Du
  • Ying Zhang
  • Yang Chen
  • Jie Zhu
  • Yi YangEmail author
  • Hong-Liang ZhangEmail author
Article

Abstract

Microglia are resident macrophage-like immune cells in the central nervous system (CNS) and play a vital role in both physiological and pathological conditions, including restoring the integrity of the CNS and promoting the progression of neurodegenerative disorders. Upon stimulation, microglia typically convert from a surveillant to an activated phenotype. The major function of microglia is to maintain homeostasis and normal function of the CNS, both during development and in response to CNS injury. Microglia regulate multiple aspects of inflammation, such as repair, cytotoxicity, regeneration, and immunosuppression due to their different kind of activation states or phenotypes. Although microglia are involved in almost all neurodegenerative disorders, the mechanisms for microglial activation and their potential contributions to neuronal degeneration remain a matter of intense debate. In inflammatory process of the CNS, polarized M1 microglia can produce proinflammatory cytokines, neurotoxic molecules, which contribute to dysfunction of neural network and promoting inflammation reaction, whereas polarized M2 microglia secrete antiinflammatory mediators and neurotrophic factors that are involved in restoring homeostasis. Modulation of microglial activation for therapeutic purposes might be realized via suppressing the deleterious effects of these cells, while simultaneously retaining their protective functions. Here, we summarize the functions of microglia and discuss dual role of microglia in neurodegenerative diseases as well as multiple sclerosis.

Keywords

Microglia Neurodegenerative disorders M1/M2 polarization Inflammation Microglial activation 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

References

  1. 1.
    Gonzalez H, Elgueta D, Montoya A, Pacheco R (2014) Neuroimmune regulation of microglial activity involved in neuroinflammation and neurodegenerative diseases. J Neuroimmunol 274(1–2):1–13. doi: 10.1016/j.jneuroim.2014.07.012 PubMedCrossRefGoogle Scholar
  2. 2.
    Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML et al (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8(6):752–758. doi: 10.1038/nn1472 PubMedCrossRefGoogle Scholar
  3. 3.
    Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308(5726):1314–1318. doi: 10.1126/science.1110647 PubMedCrossRefGoogle Scholar
  4. 4.
    Kettenmann H, Hanisch U, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91(2):461–553. doi: 10.1152/physrev.00011.2010.-Microglial PubMedCrossRefGoogle Scholar
  5. 5.
    Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10(11):1387–1394. doi: 10.1038/nn1997 PubMedCrossRefGoogle Scholar
  6. 6.
    Hanisch U (2013) Proteins in microglial activation-inputs and outputs by subsets. Curr Protein Pept Sci 14(1):3–15PubMedCrossRefGoogle Scholar
  7. 7.
    Boche D, Perry VH, Nicoll JA (2013) Review: activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol 39(1):3–18. doi: 10.1111/nan.12011 PubMedCrossRefGoogle Scholar
  8. 8.
    Ransohoff RM, Perry VH (2009) Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 27:119–145. doi: 10.1146/annurev.immunol.021908.132528 PubMedCrossRefGoogle Scholar
  9. 9.
    Ransohoff RM, Cardona AE (2010) The myeloid cells of the central nervous system parenchyma. Nature 468(7321):253–262. doi: 10.1038/nature09615 PubMedCrossRefGoogle Scholar
  10. 10.
    Chen Z, Trapp BD (2015) Microglia and neuroprotection. J Neurochem. doi: 10.1111/jnc.13062 Google Scholar
  11. 11.
    Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ et al (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330(6005):841–845. doi: 10.1126/science.1194637 PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Schulz C, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N, Kierdorf K, Prinz M, Wu B et al (2012) A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336(6077):86–90. doi: 10.1126/science.1219179 PubMedCrossRefGoogle Scholar
  13. 13.
    Hashimoto D, Chow A, Noizat C, Teo P, Beasley MB, Leboeuf M, Becker CD, See P et al (2013) Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38(4):792–804. doi: 10.1016/j.immuni.2013.04.004 PubMedCrossRefGoogle Scholar
  14. 14.
    Perdiguero EG (2014) Tissue-resident macrophages originate from yolk sac-derived erythro-myeloid progenitors. Immunology 143:26–26Google Scholar
  15. 15.
    Epelman S, Lavine KJ, Beaudin AE, Sojka DK, Carrero JA, Calderon B, Brija T, Gautier EL et al (2014) Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity 40(1):91–104. doi: 10.1016/j.immuni.2013.11.019 PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Perdiguero EG, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L, Garner H, Trouillet C et al (2015) Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518(7540):547–551. doi: 10.1038/nature13989 CrossRefGoogle Scholar
  17. 17.
    Mildner A, Schmidt H, Nitsche M, Merkler D, Hanisch UK, Mack M, Heikenwalder M, Bruck W et al (2007) Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci 10(12):1544–1553. doi: 10.1038/nn2015 PubMedCrossRefGoogle Scholar
  18. 18.
    Varvel NH, Grathwohl SA, Baumann F, Liebig C, Bosch A, Brawek B, Thal DR, Charo IF et al (2012) Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells. Proc Natl Acad Sci U S A 109(44):18150–18155. doi: 10.1073/pnas.1210150109 PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FM (2007) Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci 10(12):1538–1543. doi: 10.1038/nn2014 PubMedCrossRefGoogle Scholar
  20. 20.
    Hoeffel G, Chen J, Lavin Y, Low D, Almeida FF, See P, Beaudin AE, Lum J et al (2015) C-Myb(+) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42(4):665–678. doi: 10.1016/j.immuni.2015.03.011 PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Benarroch EE (2013) Microglia: multiple roles in surveillance, circuit shaping, and response to injury. Neurology 81(12):1079–1088. doi: 10.1212/WNL.0b013e3182a4a577 PubMedCrossRefGoogle Scholar
  22. 22.
    Nakagawa Y, Chiba K (2015) Diversity and plasticity of microglial cells in psychiatric and neurological disorders. Pharmacol Ther 154:21–35. doi: 10.1016/j.pharmthera.2015.06.010 PubMedCrossRefGoogle Scholar
  23. 23.
    Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, van Wijngaarden P, Wagers AJ et al (2013) M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 16(9):1211–1218. doi: 10.1038/nn.3469 PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Prinz M, Priller J (2014) Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci 15(5):300–312. doi: 10.1038/nrn3722 PubMedCrossRefGoogle Scholar
  25. 25.
    Suzumura A (2013) Neuron-microglia interaction in neuroinflammation. Curr Protein Pept Sci 14(1):16–20PubMedCrossRefGoogle Scholar
  26. 26.
    Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8(1):57–69. doi: 10.1038/nrn2038 PubMedCrossRefGoogle Scholar
  27. 27.
    Mahad DJ, Ransohoff RM (2003) The role of MCP-1 (CCL2) and CCR2 in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Semin Immunol 15(1):23–32PubMedCrossRefGoogle Scholar
  28. 28.
    Loane DJ, Byrnes KR (2010) Role of microglia in neurotrauma. Neurotherapeutics: the journal of the American Society for Experimental NeuroTherapeutics 7(4):366–377. doi: 10.1016/j.nurt.2010.07.002 CrossRefGoogle Scholar
  29. 29.
    David S, Kroner A (2011) Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci 12(7):388–399. doi: 10.1038/nrn3053 PubMedCrossRefGoogle Scholar
  30. 30.
    Raj DD, Jaarsma D, Holtman IR, Olah M, Ferreira FM, Schaafsma W, Brouwer N, Meijer MM et al (2014) Priming of microglia in a DNA-repair deficient model of accelerated aging. Neurobiol Aging 35(9):2147–2160. doi: 10.1016/j.neurobiolaging.2014.03.025 PubMedCrossRefGoogle Scholar
  31. 31.
    Michell-Robinson MA, Touil H, Healy LM, Owen DR, Durafourt BA, Bar-Or A, Antel JP, Moore CS (2015) Roles of microglia in brain development, tissue maintenance and repair. Brain J Neurol 138(Pt 5):1138–1159. doi: 10.1093/brain/awv066 CrossRefGoogle Scholar
  32. 32.
    Kotter MR, Li WW, Zhao C, Franklin RJ (2006) Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J Neurosci Off J Soc Neurosci 26(1):328–332. doi: 10.1523/JNEUROSCI.2615-05.2006 CrossRefGoogle Scholar
  33. 33.
    Franco R, Fernandez-Suarez D (2015) Alternatively activated microglia and macrophages in the central nervous system. Prog Neurobiol. doi: 10.1016/j.pneurobio.2015.05.003 PubMedGoogle Scholar
  34. 34.
    Lacey DC, Achuthan A, Fleetwood AJ, Dinh H, Roiniotis J, Scholz GM, Chang MW, Beckman SK et al (2012) Defining GM-CSF- and macrophage-CSF-dependent macrophage responses by in vitro models. J Immunol 188(11):5752–5765. doi: 10.4049/jimmunol.1103426 PubMedCrossRefGoogle Scholar
  35. 35.
    Weisser SB, McLarren KW, Kuroda E, Sly LM (2013) Generation and characterization of murine alternatively activated macrophages. Methods Mol Biol 946:225–239. doi: 10.1007/978-1-62703-128-8_14 PubMedCrossRefGoogle Scholar
  36. 36.
    Sierra-Filardi E, Puig-Kröger A, Blanco FJ, Nieto C, Bragado R, Palomero MI, Bernabéu C, Vega MA (2011) Activin A skews macrophage polarization by promoting a proinflammatory phenotype and inhibiting the acquisition of anti-inflammatory macrophage markers. Blood 117(19):5092–5101. doi: 10.1182/blood-201009-306993 PubMedCrossRefGoogle Scholar
  37. 37.
    Helmy A, Guilfoyle MR, Carpenter KL, Pickard JD, Menon DK, Hutchinson PJ (2015) Recombinant human interleukin-1 receptor antagonist promotes M1 microglia biased cytokines and chemokines following human traumatic brain injury. Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism. doi: 10.1177/0271678X15620204 Google Scholar
  38. 38.
    Liu Y, Luo B, Han F, Li X, Xiong J, Jiang M, Yang X, Wu Y et al (2014) Erythropoietin-derived nonerythropoietic peptide ameliorates experimental autoimmune neuritis by inflammation suppression and tissue protection. PLoS One 9(3):e90942. doi: 10.1371/journal.pone.0090942 PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Dentesano G, Serratosa J, Tusell JM, Ramon P, Valente T, Saura J, Sola C (2014) CD200R1 and CD200 expression are regulated by PPAR-gamma in activated glial cells. Glia 62(6):982–998. doi: 10.1002/glia.22656 PubMedCrossRefGoogle Scholar
  40. 40.
    Koning N, Uitdehaag BM, Huitinga I, Hoek RM (2009) Restoring immune suppression in the multiple sclerosis brain. Prog Neurobiol 89(4):359–368. doi: 10.1016/j.pneurobio.2009.09.005 PubMedCrossRefGoogle Scholar
  41. 41.
    Fitzgerald DC, Fonseca-Kelly Z, Cullimore ML, Safabakhsh P, Saris CJ, Zhang GX, Rostami A (2013) Independent and interdependent immunoregulatory effects of IL-27, IFN-beta, and IL-10 in the suppression of human Th17 cells and murine experimental autoimmune encephalomyelitis. J Immunol 190(7):3225–3234. doi: 10.4049/jimmunol.1200141 PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Jiang HR, Milovanovic M, Allan D, Niedbala W, Besnard AG, Fukada SY, Alves-Filho JC, Togbe D et al (2012) IL-33 attenuates EAE by suppressing IL-17 and IFN-gamma production and inducing alternatively activated macrophages. Eur J Immunol 42(7):1804–1814. doi: 10.1002/eji.201141947 PubMedCrossRefGoogle Scholar
  43. 43.
    Yu Z, Sun D, Feng J, Tan W, Fang X, Zhao M, Zhao X, Pu Y et al (2015) MSX3 switches microglia polarization and protects from inflammation-induced demyelination. J Neurosci 35(16):6350–6365. doi: 10.1523/jneurosci.2468-14.2015 PubMedCrossRefGoogle Scholar
  44. 44.
    Kobayashi K, Imagama S, Ohgomori T, Hirano K, Uchimura K, Sakamoto K, Hirakawa A, Takeuchi H et al (2013) Minocycline selectively inhibits M1 polarization of microglia. Cell Death Dis 4:e525. doi: 10.1038/cddis.2013.54 PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Kroner A, Greenhalgh AD, Zarruk JG, Passos Dos Santos R, Gaestel M, David S (2014) TNF and increased intracellular iron alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord. Neuron 83(5):1098–1116. doi: 10.1016/j.neuron.2014.07.027 PubMedCrossRefGoogle Scholar
  46. 46.
    Ajmone-Cat MA, Mancini M, De Simone R, Cilli P, Minghetti L (2013) Microglial polarization and plasticity: evidence from organotypic hippocampal slice cultures. Glia 61(10):1698–1711. doi: 10.1002/glia.22550 PubMedCrossRefGoogle Scholar
  47. 47.
    Zanier ER, Pischiutta F, Riganti L, Marchesi F, Turola E, Fumagalli S, Perego C, Parotto E et al (2014) Bone marrow mesenchymal stromal cells drive protective M2 microglia polarization after brain trauma. Neurotherapeutics: the journal of the American Society for Experimental NeuroTherapeutics 11(3):679–695. doi: 10.1007/s13311-014-0277-y CrossRefGoogle Scholar
  48. 48.
    Neubrand VE, Pedreno M, Caro M, Forte-Lago I, Delgado M, Gonzalez-Rey E (2014) Mesenchymal stem cells induce the ramification of microglia via the small RhoGTPases Cdc42 and Rac1. Glia 62(12):1932–1942. doi: 10.1002/glia.22714 PubMedCrossRefGoogle Scholar
  49. 49.
    Mazzon C, Zanotti L, Wang L, Del Prete A, Fontana E, Salvi V, Poliani PL, Sozzani S (2016) CCRL2 regulates M1/M2 polarization during EAE recovery phase. J Leukoc Biol. doi: 10.1189/jlb.3MA0915-444RR PubMedGoogle Scholar
  50. 50.
    He L, Marneros AG (2014) Doxycycline inhibits polarization of macrophages to the proangiogenic M2-type and subsequent neovascularization. J Biol Chem 289(12):8019–8028. doi: 10.1074/jbc.M113.535765 PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Chakrabarty P, Tianbai L, Herring A, Ceballos-Diaz C, Das P, Golde T (2012) Hippocampal expression of murine IL-4 results in exacerbation of amyloid deposition. Mol Neurodegener 7:36PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Tremblay ME, Lowery RL, Majewska AK (2010) Microglial interactions with synapses are modulated by visual experience. PLoS Biol 8(11):e1000527. doi: 10.1371/journal.pbio.1000527 PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Sierra A, Encinas JM, Deudero JJ, Chancey JH, Enikolopov G, Overstreet-Wadiche LS, Tsirka SE, Maletic-Savatic M (2010) Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7(4):483–495. doi: 10.1016/j.stem.2010.08.014 PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Marín-Teva J, Dusart I, Colin C, Gervais A, van Rooijen N, Mallat M (2004) Microglia promote the death of developing Purkinje cells. Neuron 41(4):535–547PubMedCrossRefGoogle Scholar
  55. 55.
    Marin-Teva JL, Cuadros MA, Martin-Oliva D, Navascues J (2011) Microglia and neuronal cell death. Neuron Glia Biol 7(1):25–40. doi: 10.1017/S1740925X12000014 PubMedCrossRefGoogle Scholar
  56. 56.
    Napoli I, Neumann H (2010) Protective effects of microglia in multiple sclerosis. Exp Neurol 225(1):24–28. doi: 10.1016/j.expneurol.2009.04.024 PubMedCrossRefGoogle Scholar
  57. 57.
    Fu R, Shen Q, Xu P, Luo JJ, Tang Y (2014) Phagocytosis of microglia in the central nervous system diseases. Mol Neurobiol 49(3):1422–1434. doi: 10.1007/s12035-013-8620-6 PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Piccio L, Buonsanti C, Mariani M, Cella M, Gilfillan S, Cross AH, Colonna M, Panina-Bordignon P (2007) Blockade of TREM-2 exacerbates experimental autoimmune encephalomyelitis. Eur J Immunol 37(5):1290–1301. doi: 10.1002/eji.200636837 PubMedCrossRefGoogle Scholar
  59. 59.
    Poliani PL, Wang Y, Fontana E, Robinette ML, Yamanishi Y, Gilfillan S, Colonna M (2015) TREM2 sustains microglial expansion during aging and response to demyelination. J Clin Invest 125(5):2161–2170. doi: 10.1172/jci77983ds1 PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Cantoni C, Bollman B, Licastro D, Xie M, Mikesell R, Schmidt R, Yuede CM, Galimberti D et al (2015) TREM2 regulates microglial cell activation in response to demyelination in vivo. Acta Neuropathol 129(3):429–447. doi: 10.1007/s00401-015-1388-1 PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Rayaprolu S, Mullen B, Baker M, Lynch T, Finger E, Seeley WW, Hatanpaa KJ, Lomen-Hoerth C (2013) TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson’s disease. Mol Neurodegener:8–19. doi: 10.1186/1750-1326-8-19
  62. 62.
    Cady J, Koval ED, Benitez BA, Zaidman C, Jockel-Balsarotti J, Allred P, Baloh RH, Ravits J et al (2014) TREM2 variant p.R47H as a risk factor for sporadic amyotrophic lateral sclerosis. JAMA neurology 71(4):449–453. doi: 10.1001/jamaneurol.2013.6237 PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Pottier C, Wallon D, Rousseau S, Rovelet-Lecrux A, Richard AC, Rollin-Sillaire A, Frebourg T, Campion D et al (2013) TREM2 R47H variant as a risk factor for early-onset Alzheimer’s disease. J Alzheimers Dis 35(1):45–49. doi: 10.3233/jad-122311 PubMedGoogle Scholar
  64. 64.
    Lill CM, Rengmark A, Pihlstrom L, Fogh I, Shatunov A, Sleiman PM, Wang LS, Liu T et al (2015) The role of TREM2 R47H as a risk factor for Alzheimer’s disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson’s disease. Alzheimer’s & dementia: the journal of the Alzheimer’s Association 11(12):1407–1416. doi: 10.1016/j.jalz.2014.12.009 CrossRefGoogle Scholar
  65. 65.
    Jay TR, Miller CM, Cheng PJ, Graham LC, Bemiller S, Broihier ML, Xu G, Margevicius D et al (2015) TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J Exp Med 212(3):287–295. doi: 10.1084/jem.20142322 PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Takeuchi H, Mizoguchi H, Doi Y, Jin S, Noda M, Liang J, Li H, Zhou Y et al (2011) Blockade of gap junction hemichannel suppresses disease progression in mouse models of amyotrophic lateral sclerosis and Alzheimer’s disease. PLoS One 6(6):e21108. doi: 10.1371/journal.pone.0021108 PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Sumi N, Nishioku T, Takata F, Matsumoto J, Watanabe T, Shuto H, Yamauchi A, Dohgu S et al (2010) Lipopolysaccharide-activated microglia induce dysfunction of the blood-brain barrier in rat microvascular endothelial cells co-cultured with microglia. Cell Mol Neurobiol 30(2):247–253. doi: 10.1007/s10571-009-9446-7 PubMedCrossRefGoogle Scholar
  68. 68.
    Nakajima K, Tohyama Y, Maeda S, Kohsaka S, Kurihara T (2007) Neuronal regulation by which microglia enhance the production of neurotrophic factors for GABAergic, catecholaminergic, and cholinergic neurons. Neurochem Int 50(6):807–820PubMedCrossRefGoogle Scholar
  69. 69.
    Ekdahl CT (2012) Microglial activation—tuning and pruning adult neurogenesis. Front Pharmacol 3:41. doi: 10.3389/fphar.2012.00041 PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Shigemoto-Mogami Y, Hoshikawa K, Goldman JE, Sekino Y, Sato K (2014) Microglia enhance neurogenesis and oligodendrogenesis in the early postnatal subventricular zone. J Neurosci Off J Soc Neurosci 34(6):2231–2243. doi: 10.1523/JNEUROSCI.1619-13.2014 CrossRefGoogle Scholar
  71. 71.
    Nikolakopouloua A, Duttaa R (2015) Activated microglia enhance neurogenesis via trypsinogen secretion. Proc Natl Acad Sci U S A 110(21):8714–8719CrossRefGoogle Scholar
  72. 72.
    Butovsky O, Landa G, Kunis G, Ziv Y, Avidan H, Greenberg N, Schwartz A, Smirnov I et al (2006) Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis. J Clin Invest 116(4):905–915. doi: 10.1172/JCI26836 PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Bilimoria PM, Stevens B (2015) Microglia function during brain development: new insights from animal models. Brain Res 1617:7–17. doi: 10.1016/j.brainres.2014.11.032 PubMedCrossRefGoogle Scholar
  74. 74.
    Cunningham CL, Martinez-Cerdeno V, Noctor SC (2013) Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J Neurosci Off J Soc Neurosci 33(10):4216–4233. doi: 10.1523/JNEUROSCI.3441-12.2013 CrossRefGoogle Scholar
  75. 75.
    Beggs S, Trang T, Salter MW (2012) P2X4R+ microglia drive neuropathic pain. Nat Neurosci 15(8):1068–1073. doi: 10.1038/nn.3155 PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Tsuda M, Beggs S, Salter MW, Inoue K (2013) Microglia and intractable chronic pain. Glia 61(1):55–61. doi: 10.1002/glia.22379 PubMedCrossRefGoogle Scholar
  77. 77.
    Fantin A, Vieira JM, Gestri G, Denti L, Schwarz Q, Prykhozhij S, Peri F, Wilson SW et al (2010) Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 116(5):829–840. doi: 10.1182/blood-2009-12-257832 PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Tammela T, Zarkada G, Nurmi H, Jakobsson L, Heinolainen K, Tvorogov D, Zheng W, Franco CA et al (2011) VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling. Nat Cell Biol 13(10):1202–1213. doi: 10.1038/ncb2331 PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR 3rd, Lafaille JJ, Hempstead BL, Littman DR et al (2013) Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155(7):1596–1609. doi: 10.1016/j.cell.2013.11.030 PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Norden DM, Godbout JP (2013) Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol Appl Neurobiol 39(1):19–34. doi: 10.1111/j.1365-2990.2012.01306.x PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Perry VH, Holmes C (2014) Microglial priming in neurodegenerative disease. Nat Rev Neurol 10(4):217–224. doi: 10.1038/nrneurol.2014.38 PubMedCrossRefGoogle Scholar
  82. 82.
    Streit WJ, Xue QS (2009) Life and death of microglia. J Neuroimmune Pharmacol 4(4):371–379. doi: 10.1007/s11481-009-9163-5 PubMedCrossRefGoogle Scholar
  83. 83.
    Damani MR, Zhao L, Fontainhas AM, Amaral J, Fariss RN, Wong WT (2011) Age-related alterations in the dynamic behavior of microglia. Aging Cell 10(2):263–276. doi: 10.1111/j.1474-9726.2010.00660.x PubMedCrossRefGoogle Scholar
  84. 84.
    Hefendehl JK, Neher JJ, Sühs RB, Kohsaka S, Skodras A, Jucker M (2014) Homeostatic and injury-induced microglia behavior in the aging brain. Aging Cell 13(1):60–69PubMedCrossRefGoogle Scholar
  85. 85.
    Holtman IR, Raj DD, Miller JA, Schaafsma W, Yin Z, Brouwer N, Wes PD, Moller T et al (2015) Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis. Acta Neuropathol Commun 3:31. doi: 10.1186/s40478-015-0203-5 PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Godbout JP, Chen J, Abraham J, Richwine AF, Berg BM, Kelley KW, Johnson RW (2005) Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J: Official publication of the Federation of American Societies for Experimental BiologyGoogle Scholar
  87. 87.
    Sierra A, Gottfried-Blackmore AC, McEwen BS, Bulloch K (2007) Microglia derived from aging mice exhibit an altered inflammatory profile. Glia 55(4):412–424. doi: 10.1002/glia.20468 PubMedCrossRefGoogle Scholar
  88. 88.
    Coppe JP, Desprez PY, Krtolica A, Campisi J (2010) The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 5:99–118. doi: 10.1146/annurev-pathol-121808-102144 PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Fenn AM, Henry CJ, Huang Y, Dugan A, Godbout JP (2012) Lipopolysaccharide-induced interleukin (IL)-4 receptor-alpha expression and corresponding sensitivity to the M2 promoting effects of IL-4 are impaired in microglia of aged mice. Brain Behav Immun 26(5):766–777. doi: 10.1016/j.bbi.2011.10.003 PubMedCrossRefGoogle Scholar
  90. 90.
    Henry CJ, Huang Y, Wynne AM, Godbout JP (2009) Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1beta and anti-inflammatory IL-10 cytokines. Brain Behav Immun 23(3):309–317. doi: 10.1016/j.bbi.2008.09.002 PubMedCrossRefGoogle Scholar
  91. 91.
    Olariu A, Cleaver KM, Cameron HA (2007) Decreased neurogenesis in aged rats results from loss of granule cell precursors without lengthening of the cell cycle. J Comp Neurol 501(4):659–667. doi: 10.1002/cne.21268 PubMedCrossRefGoogle Scholar
  92. 92.
    Ojo B, Rezaie P, Gabbott PL, Davies H, Colyer F, Cowley TR, Lynch M, Stewart MG (2012) Age-related changes in the hippocampus (loss of synaptophysin and glial-synaptic interaction) are modified by systemic treatment with an NCAM-derived peptide, FGL. Brain Behav Immun 26(5):778–788. doi: 10.1016/j.bbi.2011.09.013 PubMedCrossRefGoogle Scholar
  93. 93.
    Ojo B, Davies H, Rezaie P, Gabbott P, Colyer F, Kraev I, Stewart MG (2013) Age-induced loss of mossy fibre synapses on CA3 thorns in the CA3 stratum Lucidum. Neurosci J 2013:839535. doi: 10.1155/2013/839535 PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Chiu IM, Morimoto ET, Goodarzi H, Liao JT, O'Keeffe S, Phatnani HP, Muratet M, Carroll MC et al (2013) A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep 4(2):385–401. doi: 10.1016/j.celrep.2013.06.018 PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Crain JM, Nikodemova M, Watters JJ (2013) Microglia express distinct M1 and M2 phenotypic markers in the postnatal and adult central nervous system in male and female mice. J Neurosci Res 91(9):1143–1151. doi: 10.1002/jnr.23242 PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Hickman SE, Kingery ND, Ohsumi TK, Borowsky ML, Wang LC, Means TK, El Khoury J (2013) The microglial sensome revealed by direct RNA sequencing. Nat Neurosci 16(12):1896–1905. doi: 10.1038/nn.3554 PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Ma W, Cojocaru R, Gotoh N, Gieser L, Villasmil R, Cogliati T, Swaroop A, Wong WT (2013) Gene expression changes in aging retinal microglia: relationship to microglial support functions and regulation of activation. Neurobiol Aging 34(10):2310–2321. doi: 10.1016/j.neurobiolaging.2013.03.022 PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Orre M, Kamphuis W, Osborn LM, Melief J, Kooijman L, Huitinga I, Klooster J, Bossers K et al (2014) Acute isolation and transcriptome characterization of cortical astrocytes and microglia from young and aged mice. Neurobiol Aging 35(1):1–14. doi: 10.1016/j.neurobiolaging.2013.07.008 PubMedCrossRefGoogle Scholar
  99. 99.
    Wes PD, Holtman IR, Boddeke EW, Moller T, Eggen BJ (2015) Next generation transcriptomics and genomics elucidate biological complexity of microglia in health and disease. Glia. doi: 10.1002/glia.22866 PubMedGoogle Scholar
  100. 100.
    Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, Koeglsperger T, Dake B et al (2014) Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci 17(1):131–143. doi: 10.1038/nn.3599 PubMedCrossRefGoogle Scholar
  101. 101.
    Bachstetter AD, Morganti JM, Jernberg J, Schlunk A, Mitchell SH, Brewster KW, Hudson CE, Cole MJ et al (2011) Fractalkine and CX3CR1 regulate hippocampal neurogenesis in adult and aged rats. Neurobiol Aging 32(11):2030–2044. doi: 10.1016/j.neurobiolaging.2009.11.022 PubMedCrossRefGoogle Scholar
  102. 102.
    Zhang G, Li J, Purkayastha S, Tang Y, Zhang H, Yin Y, Li B, Liu G et al (2013) Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature 497(7448):211–216. doi: 10.1038/nature12143 PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, Chaudhuri AA, Kahn ME, Rao DS et al (2010) MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity 33(4):607–619. doi: 10.1016/j.immuni.2010.09.009 PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Murugaiyan G, Beynon V, Mittal A, Joller N, Weiner HL (2011) Silencing microRNA-155 ameliorates experimental autoimmune encephalomyelitis. J Immunol 187(5):2213–2221. doi: 10.4049/jimmunol.1003952 PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    von Bernhardi R, Eugenin-von Bernhardi L, Eugenin J (2015) Microglial cell dysregulation in brain aging and neurodegeneration. Front Aging Neurosci 7:124. doi: 10.3389/fnagi.2015.00124 Google Scholar
  106. 106.
    Wehrspaun CC, Haerty W, Ponting CP (2015) Microglia recapitulate a hematopoietic master regulator network in the aging human frontal cortex. Neurobiol Aging 36(8). doi: 10.1016/j.neurobiolaging.2015.04.008
  107. 107.
    Lull ME, Block ML (2010) Microglial activation and chronic neurodegeneration. Neurotherapeutics: the journal of the American Society for Experimental NeuroTherapeutics 7(4):354–365. doi: 10.1016/j.nurt.2010.05.014 CrossRefGoogle Scholar
  108. 108.
    Schuitemaker A, van der Doef TF, Boellaard R, van der Flier WM, Yaqub M, Windhorst AD, Barkhof F, Jonker C et al (2012) Microglial activation in healthy aging. Neurobiol Aging 33(6):1067–1072. doi: 10.1016/j.neurobiolaging.2010.09.016 PubMedCrossRefGoogle Scholar
  109. 109.
    Ma L, Morton AJ, Nicholson LF (2003) Microglia density decreases with age in a mouse model of Huntington’s disease. Glia 43(3):274–280. doi: 10.1002/glia.10261 PubMedCrossRefGoogle Scholar
  110. 110.
    Schwarz H, Hickey C, Zimmerman C, Mazzoni P, Moskowitz C, Rosas D, McCall M, Sanchez-Ramos J et al (2010) A futility study of minocycline in Huntington’s disease. Movement Disord 25(13):2219–2224. doi: 10.1002/mds.23236 CrossRefGoogle Scholar
  111. 111.
    Stoop MP, Rosenling T, Attali A, Meesters RJW, Stingl C, Dekker LJ, van Aken H, Suidgeest E et al (2012) Minocycline effects on the cerebrospinal fluid proteome of experimental autoimmune encephalomyelitis rats. J Proteome Res 11(8):4315–4325. doi: 10.1021/pr300428e PubMedCrossRefGoogle Scholar
  112. 112.
    Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P, Vadseth C, Choi DK, Ischiropoulos H et al (2002) Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci 22(5):1763–1771PubMedGoogle Scholar
  113. 113.
    Hunter CL, Quintero EM, Gilstrap L, Bhat NR, Granholm AC (2004) Minocycline protects basal forebrain cholinergic neurons from mu p75-saporin immunotoxic lesioning. Eur J Neurosci 19(12):3305–3316. doi: 10.1111/j.1460-9568.2004.03439.x PubMedCrossRefGoogle Scholar
  114. 114.
    Keller AF, Gravel M, Kriz J (2011) Treatment with minocycline after disease onset alters astrocyte reactivity and increases microgliosis in SOD1 mutant mice. Exp Neurol 228(1):69–79. doi: 10.1016/j.expneurol.2010.12.010 PubMedCrossRefGoogle Scholar
  115. 115.
    Cherry JD, Olschowka JA, O'Banion MK (2014) Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation 11:98. doi: 10.1186/1742-2094-11-98 PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Okello A, Edison P, Archer HA, Turkheimer FE, Kennedy J, Bullock R, Walker Z, Kennedy A (2009) Microglial activation and amyloid deposition in mild cognitive impairment. NeurologyGoogle Scholar
  117. 117.
    Yasuno F, Kosaka J, Ota M, Higuchi M, Ito H, Fujimura Y, Nozaki S, Takahashi S et al (2012) Increased binding of peripheral benzodiazepine receptor in mild cognitive impairment-dementia converters measured by positron emission tomography with [(1)(1)C]DAA1106. Psychiatry Res 203(1):67–74. doi: 10.1016/j.pscychresns.2011.08.013 PubMedCrossRefGoogle Scholar
  118. 118.
    Hickman SE, Allison EK, El Khoury J (2008) Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J Neurosci Off J Soc Neurosci 28(33):8354–8360. doi: 10.1523/JNEUROSCI.0616-08.2008 CrossRefGoogle Scholar
  119. 119.
    Lee S, Varvel NH, Konerth ME, Xu G, Cardona AE, Ransohoff RM, Lamb BT (2010) CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease mouse models. Am J Pathol 177(5):2549–2562. doi: 10.2353/ajpath.2010.100265 PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Zhao W, Zhang J, Davis EG, Rebeck GW (2014) Aging reduces glial uptake and promotes extracellular accumulation of Abeta from a lentiviral vector. Front Aging Neurosci 6:210. doi: 10.3389/fnagi.2014.00210 PubMedPubMedCentralGoogle Scholar
  121. 121.
    Karch CM, Goate AM (2015) Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry 77(1):43–51. doi: 10.1016/j.biopsych.2014.05.006 PubMedCrossRefGoogle Scholar
  122. 122.
    Mitrasinovic OM, Vincent VAM, Simsek D, Murphy GM (2003) Macrophage colony stimulating factor promotes phagocytosis by murine microglia. Neurosci Lett 344(3):185–188. doi: 10.1016/s0304-3940(03)00474-9 PubMedCrossRefGoogle Scholar
  123. 123.
    Weiner HL, Frenkel D (2006) Immunology and immunotherapy of Alzheimer’s disease. Nat Rev Immunol 6(5):404–416PubMedCrossRefGoogle Scholar
  124. 124.
    El Khoury J, Toft M, Hickman S, Geula C, Means T, Luster A (2007) Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer’s disease. Clin Immunol 123:S138. doi: 10.1016/j.clim.2007.03.030 CrossRefGoogle Scholar
  125. 125.
    Meyer-Luehmann M, Spires-Jones TL, Prada C, Garcia-Alloza M, de Calignon A, Rozkalne A, Koenigsknecht-Talboo J, Holtzman DM et al (2008) Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease. Nature 451(7179):720–724. doi: 10.1038/nature06616 PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Yokokura M, Mori N, Yagi S, Yoshikawa E, Kikuchi M, Yoshihara Y, Wakuda T, Sugihara G et al (2011) In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer’s disease. Eur J Nucl Med Mol Imaging 38(2):343–351. doi: 10.1007/s00259-010-1612-0 PubMedCrossRefGoogle Scholar
  127. 127.
    Koenigsknecht-Talboo J, Landreth GE (2005) Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J Neurosci Off J Soc Neurosci 25(36):8240–8249. doi: 10.1523/JNEUROSCI.1808-05.2005 CrossRefGoogle Scholar
  128. 128.
    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(1–2):3–12. doi: 10.1016/j.jneuroim.2009.02.003 PubMedCrossRefGoogle Scholar
  129. 129.
    Majumdar A, Cruz D, Asamoah N, Buxbaum A, Sohar I, Lobel P, Maxfield FR (2007) Activation of microglia acidifies lysosomes and leads to degradation of Alzheimer amyloid fibrils. Mol Biol Cell 18(4):1490–1496. doi: 10.1091/mbc.E06-10-0975 PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Balce DR, Li B, Allan ER, Rybicka JM, Krohn RM, Yates RM (2011) Alternative activation of macrophages by IL-4 enhances the proteolytic capacity of their phagosomes through synergistic mechanisms. Blood 118(15):4199–4208. doi: 10.1182/blood-2011-01-328906 PubMedCrossRefGoogle Scholar
  131. 131.
    Jimenez S, Baglietto-Vargas D, Caballero C, Moreno-Gonzalez I, Torres M, Sanchez-Varo R, Ruano D, Vizuete M et al (2008) Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer’s disease: age-dependent switch in the microglial phenotype from alternative to classic. J Neurosci Off J Soc Neurosci 28(45):11650–11661. doi: 10.1523/jneurosci.3024-08.2008 CrossRefGoogle Scholar
  132. 132.
    Varnum MM, Ikezu T (2012) The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer’s disease brain. Arch Immunol Ther Exp 60(4):251–266. doi: 10.1007/s00005-012-0181-2 CrossRefGoogle Scholar
  133. 133.
    He P, Zhong Z, Lindholm K, Berning L, Lee W, Lemere C, Staufenbiel M, Li R et al (2007) Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer’s mice. J Cell Biol 178(5):829–841. doi: 10.1083/jcb.200705042 PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Yamamoto M, Kiyota T, Horiba M, Buescher JL, Walsh SM, Gendelman HE, Ikezu T (2007) Interferon-gamma and tumor necrosis factor-alpha regulate amyloid-beta plaque deposition and beta-secretase expression in Swedish mutant APP transgenic mice. Am J Pathol 170(2):680–692. doi: 10.2353/ajpath.2007.060378 PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Yamamoto M, Kiyota T, Walsh SM, Liu J, Kipnis J, Ikezu T (2008) Cytokine-mediated inhibition of fibrillar amyloid-beta peptide degradation by human mononuclear phagocytes. J Immunol 181(6):3877–3886PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    von Bernhardi R, Tichauer JE, Eugenin J (2010) Aging-dependent changes of microglial cells and their relevance for neurodegenerative disorders. J Neurochem 112(5):1099–1114. doi: 10.1111/j.1471-4159.2009.06537.x CrossRefGoogle Scholar
  137. 137.
    Wang WY, Tan MS, Yu JT, Tan L (2015) Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann Transl Med 3(10):136. doi: 10.3978/j.issn.2305-5839.2015.03.49 PubMedPubMedCentralGoogle Scholar
  138. 138.
    Yan Q, Zhang J, Liu H, Babu-Khan S, Vassar R, Biere AL, Citron M, Landreth G (2003) Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer’s disease. J Neurosci Off J Soc Neurosci 23(20):7504–7509Google Scholar
  139. 139.
    Wyss-Coray T, Mucke L (2000) Ibuprofen, inflammation and Alzheimer disease. Nat Med 6(9):973–974. doi: 10.1038/79661 PubMedCrossRefGoogle Scholar
  140. 140.
    Wegiel J, Wang KC, Imaki H, Rubenstein R, Wronska A, Osuchowski M, Lipinski WJ, Walker LC et al (2001) The role of microglial cells and astrocytes in fibrillar plaque evolution in transgenic APP (SW) mice. Neurobiol Aging 22(1):49–61PubMedCrossRefGoogle Scholar
  141. 141.
    Lim GP, Yang F, Chu T, Chen P, Beech W, Teter B, Tran T, Ubeda O (2000) Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer’s disease. J Neurosci Off J Soc Neurosci 20(15):5709–5714Google Scholar
  142. 142.
    Yamanaka M, Ishikawa T, Griep A, Axt D, Kummer MP, Heneka MT (2012) PPARgamma/RXRalpha-induced and CD36-mediated microglial amyloid-beta phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice. J Neurosci Off J Soc Neurosci 32(48):17321–17331. doi: 10.1523/jneurosci.1569-12.2012 CrossRefGoogle Scholar
  143. 143.
    Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, Casali BT, Restivo JL et al (2012) ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 335(6075):1503–1506. doi: 10.1126/science.1217697 PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Varvel NH, Bhaskar K, Kounnas MZ, Wagner SL, Yang Y, Lamb BT, Herrup K (2009) NSAIDs prevent, but do not reverse, neuronal cell cycle reentry in a mouse model of Alzheimer disease. J Clin Invest 119(12):3692–3702. doi: 10.1172/jci39716 PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Imbimbo BP (2009) An update on the efficacy of non-steroidal anti-inflammatory drugs in Alzheimer’s disease. Expert opinion on investigational drugs 18(8):1147–1168. doi: 10.1517/13543780903066780 PubMedCrossRefGoogle Scholar
  146. 146.
    Gerhard A, Pavese N, Hotton G, Turkheimer F, Es M, Hammers A, Eggert K, Oertel W et al (2006) In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol Dis 21(2):404–412. doi: 10.1016/j.nbd.2005.08.002 PubMedCrossRefGoogle Scholar
  147. 147.
    Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, Wilson B, Zhang W et al (2005) Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 19(6):533–542. doi: 10.1096/fj.04-2751com CrossRefGoogle Scholar
  148. 148.
    Park JY, Paik SR, Jou I, Park SM (2008) Microglial phagocytosis is enhanced by monomeric alpha-synuclein, not aggregated alpha-synuclein: implications for Parkinson’s disease. Glia 56(11):1215–1223. doi: 10.1002/glia.20691 PubMedCrossRefGoogle Scholar
  149. 149.
    Hunot S, Hirsch EC (2003) Neuroinflammatory processes in Parkinson’s disease. Ann Neurol 53(Suppl 3):S49–S58 . doi: 10.1002/ana.10481discussion S58-60PubMedCrossRefGoogle Scholar
  150. 150.
    Long-Smith CM, Sullivan AM, Nolan YM (2009) The influence of microglia on the pathogenesis of Parkinson’s disease. Prog Neurobiol 89(3):277–287. doi: 10.1016/j.pneurobio.2009.08.001 PubMedCrossRefGoogle Scholar
  151. 151.
    Wang XJ, Ye M, Zhang YH, Chen SD (2007) CD200-CD200R regulation of microglia activation in the pathogenesis of Parkinson’s disease. J Neuroimmune Pharmacol 2(3):259–264. doi: 10.1007/s11481-007-9075-1 PubMedCrossRefGoogle Scholar
  152. 152.
    McCoy MK, Martinez TN, Ruhn KA, Szymkowski DE, Smith CG, Botterman BR, Tansey KE, Tansey MG (2006) Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson’s disease. J Neurosci Off J Soc Neurosci 26(37):9365–9375. doi: 10.1523/JNEUROSCI.1504-06.2006 CrossRefGoogle Scholar
  153. 153.
    Marinova-Mutafchieva L, Sadeghian M, Broom L, Davis JB, Medhurst AD, Dexter DT (2009) Relationship between microglial activation and dopaminergic neuronal loss in the substantia nigra: a time course study in a 6-hydroxydopamine model of Parkinson’s disease. J Neurochem 110(3):966–975. doi: 10.1111/j.1471-4159.2009.06189.x PubMedCrossRefGoogle Scholar
  154. 154.
    Zhang W, Phillips K, Wielgus AR, Liu J, Albertini A, Zucca FA, Faust R, Qian SY et al (2011) Neuromelanin activates microglia and induces degeneration of dopaminergic neurons: implications for progression of Parkinson’s disease. Neurotox Res 19(1):63–72. doi: 10.1007/s12640-009-9140-z PubMedCrossRefGoogle Scholar
  155. 155.
    Dehmer T, Heneka MT, Sastre M, Dichgans J, Schulz JB (2004) Protection by pioglitazone in the MPTP model of Parkinson’s disease correlates with I kappa B alpha induction and block of NF kappa B and iNOS activation. J Neurochem 88(2):494–501PubMedCrossRefGoogle Scholar
  156. 156.
    Carta AR, Pisanu A (2013) Modulating microglia activity with PPAR-gamma agonists: a promising therapy for Parkinson’s disease? Neurotox Res 23(2):112–123. doi: 10.1007/s12640-012-9342-7 PubMedCrossRefGoogle Scholar
  157. 157.
    Pisanu A, Lecca D, Mulas G, Wardas J, Simbula G, Spiga S, Carta AR (2014) Dynamic changes in pro- and anti-inflammatory cytokines in microglia after PPAR-gamma agonist neuroprotective treatment in the MPTPp mouse model of progressive Parkinson’s disease. Neurobiol Dis 71:280–291. doi: 10.1016/j.nbd.2014.08.011 PubMedCrossRefGoogle Scholar
  158. 158.
    Kim BW, Koppula S, Kumar H, Park JY, Kim IW, More SV, Kim IS, Han SD et al (2015) Alpha-asarone attenuates microglia-mediated neuroinflammation by inhibiting NF kappa B activation and mitigates MPTP-induced behavioral deficits in a mouse model of Parkinson’s disease. Neuropharmacology 97:46–57. doi: 10.1016/j.neuropharm.2015.04.037 PubMedCrossRefGoogle Scholar
  159. 159.
    Yang W, Chen YH, Liu H, Qu HD (2015) Neuroprotective effects of piperine on the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced Parkinson’s disease mouse model. Int J Mol Med 36(5):1369–1376. doi: 10.3892/ijmm.2015.2356 PubMedCrossRefGoogle Scholar
  160. 160.
    Machado V, Haas SJ, von Bohlen Und Halbach O, Wree A, Krieglstein K, Unsicker K, Spittau B (2016) Growth/differentiation factor-15 deficiency compromises dopaminergic neuron survival and microglial response in the 6-hydroxydopamine mouse model of Parkinson’s disease. Neurobiol Dis 88:1–15. doi: 10.1016/j.nbd.2015.12.016 PubMedCrossRefGoogle Scholar
  161. 161.
    Gagne JJ, MC. Power (2010) Anti-inflammatory drugs and risk of Parkinson disease: a meta-analysis. NeurologyGoogle Scholar
  162. 162.
    Jiang H, Li LJ, Wang J, Xie JX (2008) Ghrelin antagonizes MPTP-induced neurotoxicity to the dopaminergic neurons in mouse substantia nigra. Exp Neurol 212(2):532–537. doi: 10.1016/j.expneurol.2008.05.006 PubMedCrossRefGoogle Scholar
  163. 163.
    Moon M, Kim HG, Hwang L, Seo JH, Kim S, Hwang S, Kim S, Lee D et al (2009) Neuroprotective effect of ghrelin in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine mouse model of Parkinson’s disease by blocking microglial activation. Neurotox Res 15(4):332–347. doi: 10.1007/s12640-009-9037-x PubMedCrossRefGoogle Scholar
  164. 164.
    Ling S-C, Polymenidou M, Cleveland Don W (2013) Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79(3):416–438. doi: 10.1016/j.neuron.2013.07.033 PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Magnus T, Carmen J, Deleon J, Xue H, Pardo AC, Lepore AC, Mattson MP, Rao MS et al (2008) Adult glial precursor proliferation in mutant SOD1G93A mice. Glia 56(2):200–208. doi: 10.1002/glia.20604 PubMedCrossRefGoogle Scholar
  166. 166.
    Liao B, Zhao W, Beers DR, Henkel JS, Appel SH (2012) Transformation from a neuroprotective to a neurotoxic microglial phenotype in a mouse model of ALS. Exp Neurol 237(1):147–152. doi: 10.1016/j.expneurol.2012.06.011 PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Boillee S, Vande Velde C, Cleveland DW (2006) ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 52(1):39–59. doi: 10.1016/j.neuron.2006.09.018 PubMedCrossRefGoogle Scholar
  168. 168.
    Henkel JS, Beers DR, Siklos 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(3):427–437. doi: 10.1016/j.mcn.2005.10.016 PubMedCrossRefGoogle Scholar
  169. 169.
    Lee JC, Seong J, Kim SH, Lee SJ, Cho YJ, An J, Nam DH, Joo KM et al (2012) Replacement of microglial cells using Clodronate liposome and bone marrow transplantation in the central nervous system of SOD1(G93A) transgenic mice as an in vivo model of amyotrophic lateral sclerosis. Biochem Biophys Res Commun 418(2):359–365. doi: 10.1016/j.bbrc.2012.01.026 PubMedCrossRefGoogle Scholar
  170. 170.
    Nikodemova M, Small AL, Smith SM, Mitchell GS, Watters JJ (2014) Spinal but not cortical microglia acquire an atypical phenotype with high VEGF, galectin-3 and osteopontin, and blunted inflammatory responses in ALS rats. Neurobiol Dis 69:43–53. doi: 10.1016/j.nbd.2013.11.009 PubMedCrossRefGoogle Scholar
  171. 171.
    Boivin A, Pineau I, Barrette B, Filali M, Vallieres N, Rivest S, Lacroix S (2007) Toll-like receptor signaling is critical for Wallerian degeneration and functional recovery after peripheral nerve injury. J Neurosci Off J Soc Neurosci 27(46):12565–12576. doi: 10.1523/JNEUROSCI.3027-07.2007 CrossRefGoogle Scholar
  172. 172.
    Gowing G, Lalancette-Hebert M, Audet JN, Dequen F, Julien JP (2009) Macrophage colony stimulating factor (M-CSF) exacerbates ALS disease in a mouse model through altered responses of microglia expressing mutant superoxide dismutase. Exp Neurol 220(2):267–275. doi: 10.1016/j.expneurol.2009.08.021 PubMedCrossRefGoogle Scholar
  173. 173.
    Saba R, Gushue S, Huzarewich RL, Manguiat K, Medina S, Robertson C, Booth SA (2012) MicroRNA 146a (miR-146a) is over-expressed during prion disease and modulates the innate immune response and the microglial activation state. PLoS One 7(2):e30832. doi: 10.1371/journal.pone.0030832 PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Ponomarev ED, Veremeyko T, Weiner HL (2013) MicroRNAs are universal regulators of differentiation, activation, and polarization of microglia and macrophages in normal and diseased CNS. Glia 61(1):91–103. doi: 10.1002/glia.22363 PubMedCrossRefGoogle Scholar
  175. 175.
    Butovsky O, Siddiqui S, Gabriely G, Lanser AJ, Dake B, Murugaiyan G, Doykan CE, Wu PM et al (2012) Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J Clin Invest 122(9):3063–3087. doi: 10.1172/JCI62636 PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Butovsky O, Jedrychowski MP, Cialic R, Krasemann S, Murugaiyan G, Fanek Z, Greco DJ, Wu PM et al (2015) Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. Ann Neurol 77(1):75–99. doi: 10.1002/ana.24304 PubMedCrossRefGoogle Scholar
  177. 177.
    Tonges L, Gunther R, Suhr M, Jansen J, Balck A, Saal KA, Barski E, Nientied T et al (2014) Rho kinase inhibition modulates microglia activation and improves survival in a model of amyotrophic lateral sclerosis. Glia 62(2):217–232. doi: 10.1002/glia.22601 PubMedCrossRefGoogle Scholar
  178. 178.
    Schutz B, Reimann J, Dumitrescu-Ozimek L, Kappes-Horn K, Landreth GE, Schurmann B, Zimmer A, Heneka MT (2005) The oral antidiabetic pioglitazone protects from neurodegeneration and amyotrophic lateral sclerosis-like symptoms in superoxide dismutase-G93A transgenic mice. J Neurosci Off J Soc Neurosci 25(34):7805–7812. doi: 10.1523/jneurosci.2038-05.2005 CrossRefGoogle Scholar
  179. 179.
    Ross CA, Tabrizi SJ (2011) Huntington’s disease: from molecular pathogenesis to clinical treatment. The Lancet Neurology 10(1):83–98. doi: 10.1016/s1474-4422(10)70245-3 PubMedCrossRefGoogle Scholar
  180. 180.
    Tai YF, Pavese N, Gerhard A, Tabrizi SJ, Barker RA, Brooks DJ, Piccini P (2007) Microglial activation in presymptomatic Huntington’s disease gene carriers. Brain J Neurol 130(Pt 7):1759–1766. doi: 10.1093/brain/awm044 CrossRefGoogle Scholar
  181. 181.
    Sapp E, Kegel KB, Aronin N, Hashikawa T, Uchiyama Y, Tohyama K, Bhide PG, Vonsattel JP et al (2001) Early and progressive accumulation of reactive microglia in the Huntington disease brain. J Neuropathol Exp Neurol 60(2):161–172PubMedCrossRefGoogle Scholar
  182. 182.
    Paulsen JS, Hayden M, Stout JC, Langbehn DR, Aylward E, Ross CA, Guttman M, Nance M (2006) Preparing for preventive clinical trials: the predict-HD study. Arch Neurol 63(6):883–890PubMedCrossRefGoogle Scholar
  183. 183.
    Thevandavakkam MASR, Muchowski PJ, Giorgini F (2010) Targeting kynurenine 3-monooxygenase (KMO): implications for therapy in Huntington’s disease. CNS & neurological disorders drug targets 9(6):791–800CrossRefGoogle Scholar
  184. 184.
    Pavese N, Gerhard A, Tai YF, Ho AK, Turkheimer F, Barker RA, Brooks DJ, Piccini P (2006) Microglial activation correlates with severity in Huntington disease: a clinical and PET study. Neurology 66(11):1638–1643PubMedCrossRefGoogle Scholar
  185. 185.
    Politis M, Pavese N, Tai YF, Kiferle L, Mason SL, Brooks DJ, Tabrizi SJ, Barker RA et al (2011) Microglial activation in regions related to cognitive function predicts disease onset in Huntington’s disease: a multimodal imaging study. Hum Brain Mapp 32(2):258–270. doi: 10.1002/hbm.21008 PubMedCrossRefGoogle Scholar
  186. 186.
    Franciosi S, Ryu JK, Shim Y, Hill A, Connolly C, Hayden MR, McLarnon JG, Leavitt BR (2012) Age-dependent neurovascular abnormalities and altered microglial morphology in the YAC128 mouse model of Huntington disease. Neurobiol Dis 45(1):438–449. doi: 10.1016/j.nbd.2011.09.003 PubMedCrossRefGoogle Scholar
  187. 187.
    Kraft AD, Kaltenbach LS, Lo DC, Harry GJ (2012) Activated microglia proliferate at neurites of mutant huntingtin-expressing neurons. Neurobiol Aging 33(3) 621:e617–e633. doi: 10.1016/j.neurobiolaging.2011.02.015 CrossRefGoogle Scholar
  188. 188.
    Crotti A, Benner C, Kerman BE, Gosselin D, Lagier-Tourenne C, Zuccato C, Cattaneo E, Gage FH et al (2014) Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors. Nat Neurosci 17(4):513–521. doi: 10.1038/nn.3668 PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Palazuelos J, Aguado T, Pazos MR, Julien B, Carrasco C, Resel E, Sagredo O, Benito C et al (2009) Microglial CB2 cannabinoid receptors are neuroprotective in Huntington’s disease excitotoxicity. Brain J Neurol 132(Pt 11):3152–3164. doi: 10.1093/brain/awp239 CrossRefGoogle Scholar
  190. 190.
    Heppner FL, Greter M, Marino D, Falsig J, Raivich G, Hovelmeyer N, Waisman A, Rulicke T et al (2005) Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat Med 11(2):146–152. doi: 10.1038/nm1177 PubMedCrossRefGoogle Scholar
  191. 191.
    Bhasin M, Wu M, Tsirka SE (2007) Modulation of microglial/macrophage activation by macrophage inhibitory factor (TKP) or tuftsin (TKPR) attenuates the disease course of experimental autoimmune encephalomyelitis. BMC Immunol 8:10. doi: 10.1186/1471-2172-8-10 PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Mikita J, Dubourdieu-Cassagno N, Deloire MS, Vekris A, Biran M, Raffard G, Brochet B, Canron MH et al (2011) Altered M1/M2 activation patterns of monocytes in severe relapsing experimental rat model of multiple sclerosis. Amelioration of clinical status by M2 activated monocyte administration. Mult Scler 17(1):2–15. doi: 10.1177/1352458510379243 PubMedCrossRefGoogle Scholar
  193. 193.
    Breij EC, Brink BP, Veerhuis R, van den Berg C, Vloet R, Yan R, Dijkstra CD, van der Valk P et al (2008) Homogeneity of active demyelinating lesions in established multiple sclerosis. Ann Neurol 63(1):16–25. doi: 10.1002/ana.21311 PubMedCrossRefGoogle Scholar
  194. 194.
    Peferoen LA, Vogel DY, Ummenthum K, Breur M, Heijnen PD, Gerritsen WH, Peferoen-Baert RM, van der Valk P (2014) Activation status of human microglia is dependent on lesion formation stage and remyelination in multiple sclerosis. J Neuropathol Exp Neurol 74(1):48–63CrossRefGoogle Scholar
  195. 195.
    van Horssen J, Singh S, van der Pol S, Kipp M, Lim JL, Peferoen L, Gerritsen W, Kooi EJ et al (2012) Clusters of activated microglia in normal-appearing white matter show signs of innate immune activation. J Neuroinflammation 9:156. doi: 10.1186/1742-2094-9-156 PubMedPubMedCentralGoogle Scholar
  196. 196.
    van Noort JM, Bsibsi M, Gerritsen WH, van der Valk P, Bajramovic JJ, Steinman L, Amor S (2010) Alphab-crystallin is a target for adaptive immune responses and a trigger of innate responses in preactive multiple sclerosis lesions. J Neuropathol Exp Neurol 69(7):694–703PubMedCrossRefGoogle Scholar
  197. 197.
    Meza-Romero R, Benedek G, Yu X, Mooney JL, Dahan R, Duvshani N, Bucala R, Offner H et al (2014) HLA-DRalpha1 constructs block CD74 expression and MIF effects in experimental autoimmune encephalomyelitis. J Immunol 192(9):4164–4173. doi: 10.4049/jimmunol.1303118 PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Zhang Z, Zhang ZY, Schittenhelm J, Wu Y, Meyermann R, Schluesener HJ (2011) Parenchymal accumulation of CD163+ macrophages/microglia in multiple sclerosis brains. J Neuroimmunol 237(1–2):73–79. doi: 10.1016/j.jneuroim.2011.06.006 PubMedCrossRefGoogle Scholar
  199. 199.
    Vogel D, Vereyken E, Glim J, Heijnen P, Moeton M, van der Valk P, Amor S, Teunissen CE (2013) Macrophages in inflammatory multiple sclerosis lesions have an intermediate activation status lesions have an intermediate activation status. J Neuroinflammation 10:35PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Napoli I, Neumann H (2009) Microglial clearance function in health and disease. Neuroscience 158(3):1030–1038. doi: 10.1016/j.neuroscience.2008.06.046 PubMedCrossRefGoogle Scholar
  201. 201.
    Piccio L, Buonsanti C, Cella M, Tassi I, Schmidt RE, Fenoglio C, Rinker J 2nd, Naismith RT et al (2008) Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation. Brain J Neurol 131(Pt 11):3081–3091. doi: 10.1093/brain/awn217 CrossRefGoogle Scholar
  202. 202.
    Palazuelos J, Davoust N, Julien B, Hatterer E, Aguado T, Mechoulam R, Benito C, Romero J et al (2008) The CB(2) cannabinoid receptor controls myeloid progenitor trafficking: involvement in the pathogenesis of an animal model of multiple sclerosis. J Biol Chem 283(19):13320–13329. doi: 10.1074/jbc.M707960200 PubMedCrossRefGoogle Scholar
  203. 203.
    Hernangomez M, Mestre L, Correa FG, Loria F, Mecha M, Inigo PM, Docagne F, Williams RO et al (2012) CD200-CD200R1 interaction contributes to neuroprotective effects of anandamide on experimentally induced inflammation. Glia 60(9):1437–1450. doi: 10.1002/glia.22366 PubMedCrossRefGoogle Scholar
  204. 204.
    Kawanokuchi J, Shimizu K, Nitta A, Yamada K, Mizuno T, Takeuchi H, Suzumura A (2008) Production and functions of IL-17 in microglia. J Neuroimmunol 194(1–2):54–61. doi: 10.1016/j.jneuroim.2007.11.006 PubMedCrossRefGoogle Scholar
  205. 205.
    Olah M, Amor S, Brouwer N, Vinet J, Eggen B, Biber K, Boddeke HW (2012) Identification of a microglia phenotype supportive of remyelination. Glia 60(2):306–321. doi: 10.1002/glia.21266 PubMedCrossRefGoogle Scholar
  206. 206.
    Jackson SJ, Giovannoni G, Baker D (2011) Fingolimod modulates microglial activation to augment markers of remyelination. J Neuroinflammation 8:76. doi: 10.1186/1742-2094-8-76 PubMedPubMedCentralCrossRefGoogle Scholar
  207. 207.
    Liuzzi GM, Latronico T, Fasano A, Carlone G, Riccio P (2004) Interferon-beta inhibits the expression of metalloproteinases in rat glial cell cultures: implications for multiple sclerosis pathogenesis and treatment. Mult Scler 10(3):290–297PubMedCrossRefGoogle Scholar
  208. 208.
    Prinz M, Schmidt H, Mildner A, Knobeloch KP, Hanisch UK, Raasch J, Merkler D, Detje C et al (2008) Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system. Immunity 28(5):675–686. doi: 10.1016/j.immuni.2008.03.011 PubMedCrossRefGoogle Scholar
  209. 209.
    Ratchford JN, Endres CJ, Hammoud DA, Pomper MG, Shiee N, McGready J, Pham DL, Calabresi PA (2012) Decreased microglial activation in MS patients treated with glatiramer acetate. J Neurol 259(6):1199–1205. doi: 10.1007/s00415-011-6337-x PubMedCrossRefGoogle Scholar
  210. 210.
    Takeuchi H, Wang J, Kawanokuchi J, Mitsuma N, Mizuno T, Suzumura A (2006) Interferon-gamma induces microglial-activation-induced cell death: a hypothetical mechanism of relapse and remission in multiple sclerosis. Neurobiol Dis 22(1):33–39. doi: 10.1016/j.nbd.2005.09.014 PubMedCrossRefGoogle Scholar
  211. 211.
    Schrempf W, Ziemssen T (2007) Glatiramer acetate: mechanisms of action in multiple sclerosis. Autoimmun Rev 6(7):469–475. doi: 10.1016/j.autrev.2007.02.003 PubMedCrossRefGoogle Scholar
  212. 212.
    Kong W, Li H, Tuma RF, Ganea D (2014) Selective CB2 receptor activation ameliorates EAE by reducing Th17 differentiation and immune cell accumulation in the CNS. Cell Immunol 287(1):1–17. doi: 10.1016/j.cellimm.2013.11.002 PubMedCrossRefGoogle Scholar
  213. 213.
    Lourbopoulos A, Grigoriadis N, Lagoudaki R, Touloumi O, Polyzoidou E, Mavromatis I, Tascos N, Breuer A et al (2011) Administration of 2-arachidonoylglycerol ameliorates both acute and chronic experimental autoimmune encephalomyelitis. Brain Res 1390:126–141. doi: 10.1016/j.brainres.2011.03.020 PubMedCrossRefGoogle Scholar
  214. 214.
    Liu Y, Holdbrooks AT, De Sarno P, Rowse AL, Yanagisawa LL, McFarland BC, Harrington LE, Raman C et al (2014) Therapeutic efficacy of suppressing the Jak/STAT pathway in multiple models of experimental autoimmune encephalomyelitis. J Immunol 192(1):59–72. doi: 10.4049/jimmunol.1301513 PubMedCrossRefGoogle Scholar
  215. 215.
    Popovic N, Schubart A, Goetz BD, Zhang SC, Linington C, Duncan ID (2002) Inhibition of autoimmune encephalomyelitis by a tetracycline. Ann Neurol 51(2):215–223PubMedCrossRefGoogle Scholar
  216. 216.
    Wilms H, Sievers J, Rickert U, Rostami-Yazdi M, Mrowietz U, Lucius R (2010) Dimethylfumarate inhibits microglial and astrocytic inflammation by suppressing the synthesis of nitric oxide, IL-1beta, TNF-alpha and IL-6 in an in-vitro model of brain inflammation. J Neuroinflammation 7:30. doi: 10.1186/1742-2094-7-30 PubMedPubMedCentralCrossRefGoogle Scholar
  217. 217.
    Zhou J, Cai W, Jin M, Xu J, Wang Y, Xiao Y, Hao L, Wang B et al (2015) 18beta-glycyrrhetinic acid suppresses experimental autoimmune encephalomyelitis through inhibition of microglia activation and promotion of remyelination. Scientific reports 5:13713. doi: 10.1038/srep13713 PubMedPubMedCentralCrossRefGoogle Scholar
  218. 218.
    Imai F, Suzuki H, Oda J, Ninomiya T, Ono K, Sano H, Sawada M (2007) Neuroprotective effect of exogenous microglia in global brain ischemia. Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 27(3):488–500. doi: 10.1038/sj.jcbfm.9600362 CrossRefGoogle Scholar
  219. 219.
    Ribot E, Bouzier-Sore AK, Bouchaud V, Miraux S, Delville MH, Franconi JM, Voisin P (2007) Microglia used as vehicles for both inducible thymidine kinase gene therapy and MRI contrast agents for glioma therapy. Cancer Gene Ther 14(8):724–737. doi: 10.1038/sj.cgt.7701060 PubMedCrossRefGoogle Scholar
  220. 220.
    Laroni A, Novi G, Kerlero de Rosbo N, Uccelli A (2013) Towards clinical application of mesenchymal stem cells for treatment of neurological diseases of the central nervous system. J Neuroimmune Pharmacol 8(5):1062–1076. doi: 10.1007/s11481-013-9456-6 PubMedCrossRefGoogle Scholar
  221. 221.
    Ho L, Qin W, Stetka BS, Pasinetti GM (2006) Is there a future for cyclo-oxygenase inhibitors in Alzheimer’s disease? CNS drugs 20(2):85–98PubMedCrossRefGoogle Scholar
  222. 222.
    Chen H, Jacobs E, Schwarzschild MA, McCullough ML, Calle EE, Thun MJ, Ascherio A (2005) Nonsteroidal antiinflammatory drug use and the risk for Parkinson’s disease. Ann Neurol 58(6):963–967. doi: 10.1002/ana.20682 PubMedCrossRefGoogle Scholar
  223. 223.
    Samii A, Etminan M, Wiens MO, Jafari S (2009) NSAID use and the risk of Parkinson’s disease: systematic review and meta-analysis of observational studies. Drugs Aging 26(9):769–779. doi: 10.2165/11316780-000000000-00000 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Neuroscience Center, Department of NeurologyThe First Hospital of Jilin University, Jilin UniversityChangchunChina
  2. 2.Department of Neurobiology, Care Sciences and SocietyKarolinska InstituteStockholmSweden
  3. 3.Department of Life Sciencesthe National Natural Science Foundation of ChinaBeijingChina

Personalised recommendations