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

Molecular Neurobiology

Volumn 54, Issue 10, 2017, Pages 7567-7584

  Du, Li ^a   Zhang, Ying ^a   Chen, Yang ^a   Zhu, Jie ^a,b   Yang, Yi ^a   Zhang, Hong Liang ^a,c  

^a THE FIRST HOSPITAL OF JILIN UNIVERSITY   (China)

^b KAROLINSKA INSTITUTE   (Sweden)

^c NATIONAL NATURAL SCIENCE FOUNDATION OF CHINA   (China)

Author keywords

Inflammation; M1 M2 polarization; Microglia; Microglial activation; Neurodegenerative disorders

Indexed keywords

ALPHA ASARONE; BETA INTERFERON; BEXAROTENE; CYTOKINE; FINGOLIMOD; FUMARIC ACID DIMETHYL ESTER; GHRELIN; GLATIRAMER; GLUCOCORTICOID; GLYCYRRHETINIC ACID; IBUPROFEN; INTERLEUKIN 10; INTERLEUKIN 33; MINOCYCLINE; NALOXONE; NAPROXEN; NONSTEROID ANTIINFLAMMATORY AGENT; OXIDOPAMINE; PIOGLITAZONE; PIPERINE; ROSIGLITAZONE; AUTACOID; NERVE GROWTH FACTOR; NEUROPROTECTIVE AGENT;

AGING; ALZHEIMER DISEASE; AMYOTROPHIC LATERAL SCLEROSIS; CELL ACTIVATION; CELL FUNCTION; DEGENERATIVE DISEASE; DRUG MECHANISM; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; HUMAN; HUNTINGTON CHOREA; INFLAMMATION; MICROGLIA; MULTIPLE SCLEROSIS; NEUROPATHOLOGY; NONHUMAN; PARKINSON DISEASE; POLARIZATION; REVIEW; ANIMAL; ANTAGONISTS AND INHIBITORS; DRUG EFFECT; IMMUNOLOGY; METABOLISM; NEUROLOGIC DISEASE; PHYSIOLOGY;

ANIMALS; HUMANS; INFLAMMATION MEDIATORS; MICROGLIA; NERVE GROWTH FACTORS; NERVOUS SYSTEM DISEASES; NEUROPROTECTIVE AGENTS;

EID: 84994404332     PISSN: 08937648     EISSN: 15591182     Source Type: Journal    
DOI: 10.1007/s12035-016-0245-0     Document Type: Review

References (223)

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
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
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
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
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
6. Hanisch U (2013) Proteins in microglial activation-inputs and outputs by subsets. Curr Protein Pept Sci 14(1):3–15
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
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
9. Ransohoff RM, Cardona AE (2010) The myeloid cells of the central nervous system parenchyma. Nature 468(7321):253–262. doi:10.1038/nature09615
10. Chen Z, Trapp BD (2015) Microglia and neuroprotection. J Neurochem. doi:10.1111/jnc.13062
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
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
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
14. Perdiguero EG (2014) Tissue-resident macrophages originate from yolk sac-derived erythro-myeloid progenitors. Immunology 143:26–26
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
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
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
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
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
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
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
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
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
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
25. Suzumura A (2013) Neuron-microglia interaction in neuroinflammation. Curr Protein Pept Sci 14(1):16–20
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
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):23–32
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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 7:36
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
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
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):535–547
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
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
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
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
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
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
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. 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
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
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
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
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
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
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):807–820
69. Ekdahl CT (2012) Microglial activation—tuning and pruning adult neurogenesis. Front Pharmacol 3:41. doi:10.3389/fphar.2012.00041
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
71. Nikolakopouloua A, Duttaa R (2015) Activated microglia enhance neurogenesis via trypsinogen secretion. Proc Natl Acad Sci U S A 110(21):8714–8719
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
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
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
75. Beggs S, Trang T, Salter MW (2012) P2X4R+ microglia drive neuropathic pain. Nat Neurosci 15(8):1068–1073. doi:10.1038/nn.3155
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
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
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
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
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
81. Perry VH, Holmes C (2014) Microglial priming in neurodegenerative disease. Nat Rev Neurol 10(4):217–224. doi:10.1038/nrneurol.2014.38
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
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
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):60–69
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
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 Biology
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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. 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
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
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
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
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
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):1763–1771
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
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
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
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. Neurology
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
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
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
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
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
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
123. Weiner HL, Frenkel D (2006) Immunology and immunotherapy of Alzheimer’s disease. Nat Rev Immunol 6(5):404–416
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
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
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
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
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
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
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
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
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
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
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
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):3877–3886
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
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
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):7504–7509
139. Wyss-Coray T, Mucke L (2000) Ibuprofen, inflammation and Alzheimer disease. Nat Med 6(9):973–974. doi:10.1038/79661
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):49–61
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):5709–5714
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
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
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
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
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
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
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
149. Hunot S, Hirsch EC (2003) Neuroinflammatory processes in Parkinson’s disease. Ann Neurol 53(Suppl 3):S49–S58. doi:10.1002/ana.10481discussion S58-60
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
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
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
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
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
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):494–501
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
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
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
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
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
161. Gagne JJ, MC. Power (2010) Anti-inflammatory drugs and risk of Parkinson disease: a meta-analysis. Neurology
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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):161–172
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):883–890
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):791–800
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):1638–1643
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
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
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
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
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
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
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
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
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
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):48–63
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
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):694–703
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
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
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 10:35
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
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
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
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
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
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
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
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):290–297
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
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
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
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
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
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
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
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):215–223
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
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
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
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
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
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):85–98
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
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