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.
Similar content being viewed by others
References
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
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
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
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
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
Hanisch U (2013) Proteins in microglial activation-inputs and outputs by subsets. Curr Protein Pept Sci 14(1):3–15
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
Ransohoff RM, Perry VH (2009) Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 27:119–145. doi:10.1146/annurev.immunol.021908.132528
Ransohoff RM, Cardona AE (2010) The myeloid cells of the central nervous system parenchyma. Nature 468(7321):253–262. doi:10.1038/nature09615
Chen Z, Trapp BD (2015) Microglia and neuroprotection. J Neurochem. doi:10.1111/jnc.13062
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
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
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
Perdiguero EG (2014) Tissue-resident macrophages originate from yolk sac-derived erythro-myeloid progenitors. Immunology 143:26–26
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
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
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
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
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
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
Benarroch EE (2013) Microglia: multiple roles in surveillance, circuit shaping, and response to injury. Neurology 81(12):1079–1088. doi:10.1212/WNL.0b013e3182a4a577
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
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
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
Suzumura A (2013) Neuron-microglia interaction in neuroinflammation. Curr Protein Pept Sci 14(1):16–20
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Ekdahl CT (2012) Microglial activation—tuning and pruning adult neurogenesis. Front Pharmacol 3:41. doi:10.3389/fphar.2012.00041
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
Nikolakopouloua A, Duttaa R (2015) Activated microglia enhance neurogenesis via trypsinogen secretion. Proc Natl Acad Sci U S A 110(21):8714–8719
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
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
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
Beggs S, Trang T, Salter MW (2012) P2X4R+ microglia drive neuropathic pain. Nat Neurosci 15(8):1068–1073. doi:10.1038/nn.3155
Tsuda M, Beggs S, Salter MW, Inoue K (2013) Microglia and intractable chronic pain. Glia 61(1):55–61. doi:10.1002/glia.22379
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
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
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
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
Perry VH, Holmes C (2014) Microglial priming in neurodegenerative disease. Nat Rev Neurol 10(4):217–224. doi:10.1038/nrneurol.2014.38
Streit WJ, Xue QS (2009) Life and death of microglia. J Neuroimmune Pharmacol 4(4):371–379. doi:10.1007/s11481-009-9163-5
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Weiner HL, Frenkel D (2006) Immunology and immunotherapy of Alzheimer’s disease. Nat Rev Immunol 6(5):404–416
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Wyss-Coray T, Mucke L (2000) Ibuprofen, inflammation and Alzheimer disease. Nat Med 6(9):973–974. doi:10.1038/79661
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Gagne JJ, MC. Power (2010) Anti-inflammatory drugs and risk of Parkinson disease: a meta-analysis. Neurology
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of Interest
The authors declare that they have no conflicts of interest.
Rights and permissions
About this article
Cite this article
Du, L., Zhang, Y., Chen, Y. et al. Role of Microglia in Neurological Disorders and Their Potentials as a Therapeutic Target. Mol Neurobiol 54, 7567–7584 (2017). https://doi.org/10.1007/s12035-016-0245-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12035-016-0245-0