Abstract
Huntington’s disease (HD) is a monogenic neurodegenerative disease characterized by abnormal motor movements, personality changes and early death. In contrast to other neurodegenerative diseases, very little is known about the role of neuroinflammation in HD. While the current data clearly demonstrate the existence of inflammatory processes in HD pathophysiology, the question of whether neuroinflammation is purely reactive or might actively participate in disease pathogenesis is currently a matter of ongoing research and debate. This review will try to shed some light on the current state of research in this area and provide an outlook on potential future developments.
Similar content being viewed by others
References
Amori L, Guidetti P, Pellicciari R, Kajii Y, Schwarcz R (2009) On the relationship between the two branches of the kynurenine pathway in the rat brain in vivo. J Neurochem 109:316–325
Andrade MA, Bork P (1995) HEAT repeats in the Huntington’s disease protein. Nat Genet 11:115–116
Andrew SE, Goldberg YP, Kremer B, Telenius H, Theilmann J, Adam S, Starr E, Squitieri F, Lin B, Kalchman MA et al (1993) The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington’s disease. Nat Genet 4:398–403
Appel SH, Beers DR, Henkel JS (2010) T cell-microglial dialogue in Parkinson’s disease and amyotrophic lateral sclerosis: are we listening? Trends Immunol 31:7–17
Beal MF, Ferrante RJ (2004) Experimental therapeutics in transgenic mouse models of Huntington’s disease. Nat Rev Neurosci 5:373–384
Bezprozvanny I (2007) Inositol 1,4,5-tripshosphate receptor, calcium signalling and Huntington’s disease. Subcell Biochem 45:323–335
Bezprozvanny I (2009) Calcium signaling and neurodegenerative diseases. Trends Mol Med 15:89–100
Bjorkqvist M et al (2008) A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington’s disease. J Exp Med 205:1869–1877
Blum D, Chtarto A, Tenenbaum L, Brotchi J, Levivier M (2004) Clinical potential of minocycline for neurodegenerative disorders. Neurobiol Dis 17:359–366
Bonifati DM, Kishore U (2007) Role of complement in neurodegeneration and neuroinflammation. Mol Immunol 44:999–1010
Bradford J, Shin JY, Roberts M, Wang CE, Li XJ, Li S (2009) Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms. Proc Natl Acad Sci USA 106:22480–22485
Bradford J, Shin JY, Roberts M, Wang CE, Sheng G, Li S, Li XJ (2010) Mutant huntingtin in glial cells exacerbates neurological symptoms of Huntington disease mice. J Biol Chem 285:10653–10661
Buraczynska MJ, Van Keuren ML, Buraczynska KM, Chang YS, Crombez E, Kurnit DM (1995) Construction of human embryonic cDNA libraries: HD, PKD1 and BRCA1 are transcribed widely during embryogenesis. Cytogenet Cell Genet 71:197–202
Cagnin A, Kassiou M, Meikle SR, Banati RB (2007) Positron emission tomography imaging of neuroinflammation. Neurotherapeutics 4:443–452
Carroll MC (2004) The complement system in regulation of adaptive immunity. Nat Immunol 5:981–986
Carson MJ (2002) Microglia as liaisons between the immune and central nervous system: functional implications in multiple sclerosis. Glia 40:218–231
Cattaneo E, Rigamonti D, Goffredo D, Zuccato C, Squitieri F, Sipione S (2001) Loss of normal huntingtin function: new developments in Huntington’s disease research. Trends Neurosci 24:182–188
Cattaneo E, Zuccato C, Tartari M (2005) Normal huntingtin function: an alternative approach to Huntington’s disease. Nat Rev Neurosci 6:919–930
Cha JH (2007) Transcriptional signatures in Huntington’s disease. Prog Neurobiol 83:228–248
Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, Bian J, Guo L, Farrell LA, Hersch SM, Hobbs W, Vonsattel JP, Cha JH, Friedlander RM (2000) Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 6:797–801
Curtis AR, Fey C, Morris CM, Bindoff LA, Ince PG, Chinnery PF, Coulthard A, Jackson MJ, Jackson AP, McHale DP, Hay D, Barker WA, Markham AF, Bates D, Curtis A, Burn J (2001) Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat Genet 28:350–354
Dexter DT, Carayon A, Javoy-Agid F, Agid Y, Wells FR, Daniel SE, Lees AJ, Jenner P, Marsden CD (1991) Alterations in the levels of iron, ferritin and other trace metals in Parkinson’s disease and other neurodegenerative diseases affecting the basal ganglia. Brain 114(Pt 4):1953–1975
Dinarello CA (2006) Inhibitors of histone deacetylases as anti-inflammatory drugs. Ernst Schering Res Found Workshop 56:45–60
Farber K, Kettenmann H (2006) Functional role of calcium signals for microglial function. Glia 54:656–665
Ferrante RJ (2009) Mouse models of Huntington’s disease and methodological considerations for therapeutic trials. Biochim Biophys Acta 1792:506–520
Firdaus WJ, Wyttenbach A, Giuliano P, Kretz-Remy C, Currie RW, Arrigo AP (2006) Huntingtin inclusion bodies are iron-dependent centers of oxidative events. FEBS J 273:5428–5441
Garden GA (2002) Microglia in human immunodeficiency virus-associated neurodegeneration. Glia 40:240–251
Garden GA, Möller T (2006) Microglia biology in health and disease. J Neuroimmune Pharmacol 1:127–137
Gil JM, Rego AC (2009) The R6 lines of transgenic mice: a model for screening new therapies for Huntington’s disease. Brain Res Rev 59:410–431
Giorgini F (2008) The kynurenine pathway and microglia: implications for pathology and therapy in Huntington’s disease. In: Outerio TF (ed) Proteinmisfolding in biology and disease. Transworld Research Network, Kerala, pp 231–255
Giorgini F, Guidetti P, Nguyen Q, Bennett SC, Muchowski PJ (2005) A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease. Nat Genet 37:526–531
Giorgini F, Moller T, Kwan W, Zwilling D, Wacker JL, Hong S, Tsai LC, Cheah CS, Schwarcz R, Guidetti P, Muchowski PJ (2008) Histone deacetylase inhibition modulates kynurenine pathway activation in yeast, microglia, and mice expressing a mutant huntingtin fragment. J Biol Chem 283:7390–7400
Goehler H et al (2004) A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington’s disease. Mol cell 15:853–865
Griffiths MR, Gasque P, Neal JW (2009) The multiple roles of the innate immune system in the regulation of apoptosis and inflammation in the brain. J Neuropathol Exp Neurol 68:217–226
Gu X, Li C, Wei W, Lo V, Gong S, Li SH, Iwasato T, Itohara S, Li XJ, Mody I, Heintz N, Yang XW (2005) Pathological cell–cell interactions elicited by a neuropathogenic form of mutant Huntingtin contribute to cortical pathogenesis in HD mice. Neuron 46:433–444
Gu X, Andre VM, Cepeda C, Li SH, Li XJ, Levine MS, Yang XW (2007) Pathological cell–cell interactions are necessary for striatal pathogenesis in a conditional mouse model of Huntington’s disease. Mol neurodegener 2:8
Guillemin GJ, Smith DG, Smythe GA, Armati PJ, Brew BJ (2003) Expression of the kynurenine pathway enzymes in human microglia and macrophages. Adv Exp Med Biol 527:105–112
Gusella JF, MacDonald ME (2000) Molecular genetics: unmasking polyglutamine triggers in neurodegenerative disease. Nat Rev Neurosci 1:109–115
Gusella JF, Macdonald ME (2006) Huntington’s disease: seeing the pathogenic process through a genetic lens. Trends Biochem Sci 31:533–540
Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394
Hanisch U-K, Kohsaka S, Möller T (eds) (2002) Special issue microglia. Wiely-Liss, New York
Harry GJ, Kraft AD (2008) Neuroinflammation and microglia: considerations and approaches for neurotoxicity assessment. Expert Opin Drug Metab Toxicol 4:1265–1277
Hauwel M, Furon E, Canova C, Griffiths M, Neal J, Gasque P (2005) Innate (inherent) control of brain infection, brain inflammation and brain repair: the role of microglia, astrocytes, “protective” glial stem cells and stromal ependymal cells. Brain Res Brain Res Rev 48:220–233
HDCR Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983
Hersch SM, Ferrante RJ (2004) Translating therapies for Huntington’s disease from genetic animal models to clinical trials. NeuroRx 1:298–306
Hertz L, Zhao Z, Chen Y (2006) The astrocytic GABA(A)/benzodiazepine-like receptor: the Joker receptor for benzodiazepine-mimetic drugs? Recent Pat CNS Drug Discov 1:93–103
Hilditch-Maguire P, Trettel F, Passani LA, Auerbach A, Persichetti F, MacDonald ME (2000) Huntingtin: an iron-regulated protein essential for normal nuclear and perinuclear organelles. Hum Mol Genet 9:2789–2797
Hirsch EC, Hunot S (2009) Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol 8:382–397
Hockly E, Richon VM, Woodman B, Smith DL, Zhou X, Rosa E, Sathasivam K, Ghazi-Noori S, Mahal A, Lowden PA, Steffan JS, Marsh JL, Thompson LM, Lewis CM, Marks PA, Bates GP (2003) Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington’s disease. Proc Natl Acad Sci USA 100:2041–2046
Hoffmann A, Kann O, Ohlemeyer C, Hanisch UK, Kettenmann H (2003) Elevation of basal intracellular calcium as a central element in the activation of brain macrophages (microglia): suppression of receptor-evoked calcium signaling and control of release function. J Neurosci 23:4410–4419
Im SH, Rao A (2004) Activation and deactivation of gene expression by Ca2+/calcineurin-NFAT-mediated signaling. Mol Cells 18:1–9
Imarisio S, Carmichael J, Korolchuk V, Chen CW, Saiki S, Rose C, Krishna G, Davies JE, Ttofi E, Underwood BR, Rubinsztein DC (2008) Huntington’s disease: from pathology and genetics to potential therapies. Biochem J 412:191–209
Kim YS, Joh TH (2006) Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson’s disease. Exp Mol Med 38:333–347
Kim HS, Suh YH (2009) Minocycline and neurodegenerative diseases. Behav Brain Res 196:168–179
Kim HJ, Rowe M, Ren M, Hong JS, Chen PS, Chuang DM (2007) Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action. J Pharmacol Exp Ther 321:892–901
Kuhn A et al (2007) Mutant huntingtin’s effects on striatal gene expression in mice recapitulate changes observed in human Huntington’s disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage. Hum Mol Genet 16:1845–1861
Li SH, Li XJ (2004) Huntingtin–protein interactions and the pathogenesis of Huntington’s disease. Trends Genet 20:146–154
Li SH, Schilling G, Young WS 3rd, Li XJ, Margolis RL, Stine OC, Wagster MV, Abbott MH, Franz ML, Ranen NG et al (1993) Huntington’s disease gene (IT15) is widely expressed in human and rat tissues. Neuron 11:985–993
Lin CH, Tallaksen-Greene S, Chien WM, Cearley JA, Jackson WS, Crouse AB, Ren S, Li XJ, Albin RL, Detloff PJ (2001) Neurological abnormalities in a knock-in mouse model of Huntington’s disease. Hum Mol Genet 10:137–144
Lobsiger CS, Cleveland DW (2007) Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease. Nat Neurosci 10:1355–1360
Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, Bates GP (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87:493–506
Mievis S, Levivier M, Communi D, Vassart G, Brotchi J, Ledent C, Blum D (2007) Lack of minocycline efficiency in genetic models of Huntington’s disease. Neuromolecular Med 9:47–54
Möller T (2002) Calcium signaling in microglial cells. Glia 40:184–194
Möller T, Nolte C, Burger R, Verkhratsky A, Kettenmann H (1997) Mechanisms of C5a and C3a complement fragment-induced [Ca2+]i signaling in mouse microglia. J Neurosci 17:615–624
Moroni F (1999) Tryptophan metabolism and brain function: focus on kynurenine and other indole metabolites. Eur J Pharmacol 375:87–100
Nolte C, Moller T, Walter T, Kettenmann H (1996) Complement 5a controls motility of murine microglial cells in vitro via activation of an inhibitory G-protein and the rearrangement of the actin cytoskeleton. Neuroscience 73:1091–1107
Orr HT, Zoghbi HY (2007) Trinucleotide repeat disorders. Annu Rev Neurosci 30:575–621
Orsucci D, Calsolaro V, Mancuso M, Siciliano G (2009) Neuroprotective effects of tetracyclines: molecular targets, animal models and human disease. CNS Neurol Disord Drug Targets 8:222–231
Palazuelos J, Aguado T, Pazos MR, Julien B, Carrasco C, Resel E, Sagredo O, Benito C, Romero J, Azcoitia I, Fernandez-Ruiz J, Guzman M, Galve-Roperh I (2009) Microglial CB2 cannabinoid receptors are neuroprotective in Huntington’s disease excitotoxicity. Brain 132:3152–3164
Panov AV, Gutekunst CA, Leavitt BR, Hayden MR, Burke JR, Strittmatter WJ, Greenamyre JT (2002) Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nat Neurosci 5:731–736
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 66:1638–1643
Przedborski S (2007) Neuroinflammation and Parkinson’s disease. Handb Clin Neurol 83:535–551
Quintana A, Griesemer D, Schwarz EC, Hoth M (2005) Calcium-dependent activation of T-lymphocytes. Pflugers Arch 450:1–12
Ransohoff RM, Perry VH (2009) Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 27:119–145
Rogers J (2008) The inflammatory response in Alzheimer’s disease. J Periodontol 79:1535–1543
Roze E, Saudou F, Caboche J (2008) Pathophysiology of Huntington’s disease: from huntingtin functions to potential treatments. Curr Opin Neurol 21:497–503
Sapp E, Kegel KB, Aronin N, Hashikawa T, Uchiyama Y, Tohyama K, Bhide PG, Vonsattel JP, DiFiglia M (2001) Early and progressive accumulation of reactive microglia in the Huntington disease brain. J Neuropathol Exp Neurol 60:161–172
Schwarcz R (2004) The kynurenine pathway of tryptophan degradation as a drug target. Curr Opin Pharmacol 4:12–17
Schwarcz R, Pellicciari R (2002) Manipulation of brain kynurenines: glial targets, neuronal effects, and clinical opportunities. J Pharmacol Exp Ther 303:1–10
Schwarcz R, Whetsell WO Jr, Mangano RM (1983) Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain. Science 219:316–318
Schwarcz R, Guidetti P, Sathyasaikumar KV, Muchowski PJ (2010) Of mice, rats and men: revisiting the quinolinic acid hypothesis of Huntington’s disease. Prog Neurobiol 90:230–245
Shin JY, Fang ZH, Yu ZX, Wang CE, Li SH, Li XJ (2005) Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity. J Cell Biol 171:1001–1012
Shoham S, Youdim MB (2000) Iron involvement in neural damage and microgliosis in models of neurodegenerative diseases. Cell Mol Biol (Noisy-le-Grand, France) 46:743–760
Silvestroni A, Faull RL, Strand AD, Moller T (2009) Distinct neuroinflammatory profile in post-mortem human Huntington’s disease. Neuroreport 20:1098–1103
Simmons DA, Casale M, Alcon B, Pham N, Narayan N, Lynch G (2007) Ferritin accumulation in dystrophic microglia is an early event in the development of Huntington’s disease. Glia 55:1074–1084
Singhrao SK, Neal JW, Morgan BP, Gasque P (1999) Increased complement biosynthesis by microglia and complement activation on neurons in Huntington’s disease. Exp Neurol 159:362–376
Slow EJ, van Raamsdonk J, Rogers D, Coleman SH, Graham RK, Deng Y, Oh R, Bissada N, Hossain SM, Yang YZ, Li XJ, Simpson EM, Gutekunst CA, Leavitt BR, Hayden MR (2003) Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum Mol Genet 12:1555–1567
Snell RG, MacMillan JC, Cheadle JP, Fenton I, Lazarou LP, Davies P, MacDonald ME, Gusella JF, Harper PS, Shaw DJ (1993) Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington’s disease. Nat Genet 4:393–397
Stack EC, Smith KM, Ryu H, Cormier K, Chen M, Hagerty SW, Del Signore SJ, Cudkowicz ME, Friedlander RM, Ferrante RJ (2006) Combination therapy using minocycline and coenzyme Q10 in R6/2 transgenic Huntington’s disease mice. Biochim Biophys Acta 1762:373–380
Stella N (2009) Endocannabinoid signaling in microglial cells. Neuropharmacology 56(Suppl 1):244–253
Streit WJ (2005) Microglia and neuroprotection: implications for Alzheimer’s disease. Brain Res Brain Res Rev 48:234–239
Sugama S, Takenouchi T, Cho BP, Joh TH, Hashimoto M, Kitani H (2009) Possible roles of microglial cells for neurotoxicity in clinical neurodegenerative diseases and experimental animal models. Inflamm Allergy Drug Targets 8:277–284
Tai YF, Pavese N, Gerhard A, Tabrizi SJ, Barker RA, Brooks DJ, Piccini P (2007a) Imaging microglial activation in Huntington’s disease. Brain Res Bull 72:148–151
Tai YF, Pavese N, Gerhard A, Tabrizi SJ, Barker RA, Brooks DJ, Piccini P (2007b) Microglial activation in presymptomatic Huntington’s disease gene carriers. Brain 130:1759–1766
Tang TS, Slow E, Lupu V, Stavrovskaya IG, Sugimori M, Llinas R, Kristal BS, Hayden MR, Bezprozvanny I (2005) Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington’s disease. Proc Natl Acad Sci USA 102:2602–2607
Theurl I, Fritsche G, Ludwiczek S, Garimorth K, Bellmann-Weiler R, Weiss G (2005) The macrophage: a cellular factory at the interphase between iron and immunity for the control of infections. Biometals 18:359–367
Thomas EA, Coppola G, Desplats PA, Tang B, Soragni E, Burnett R, Gao F, Fitzgerald KM, Borok JF, Herman D, Geschwind DH, Gottesfeld JM (2008) The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington’s disease transgenic mice. Proc Natl Acad Sci USA 105:15564–15569
Trottier Y, Devys D, Imbert G, Saudou F, An I, Lutz Y, Weber C, Agid Y, Hirsch EC, Mandel JL (1995) Cellular localization of the Huntington’s disease protein and discrimination of the normal and mutated form. Nat Genet 10:104–110
van Rossum D, Hanisch UK (2004) Microglia. Metab Brain Dis 19:393–411
Vonsattel JP, DiFiglia M (1998) Huntington disease. J Neuropathol Exp Neurol 57:369–384
Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP Jr (1985) Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 44:559–577
Walker FO (2007) Huntington’s disease. Semin Neurol 27:143–150
Weinstein JR, Koerner IP, Möller T (2010) Microglia in ischemic brain injury. Future Neurol 5:227–246
Weydt P, Möller T (2005) The role of microglial cells in amyotrophic lateral sclerosis. Phys Med Rehabil Clin N Am 16:1081–1090 (xi)
Wyss-Coray T (2006) Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 12:1005–1015
Zhang X, Surguladze N, Slagle-Webb B, Cozzi A, Connor JR (2006) Cellular iron status influences the functional relationship between microglia and oligodendrocytes. Glia 54:795–804
Acknowledgments
I would like to thank Dr. Flaviano Giorgini, University of Leicester, UK for valuable comments on the manuscript; Dr. Paul Muchowski (Gladstone Institute of Neurological Disease, UCSF) for drawing my attention to HD research; and the CHDI Foundation for providing support for our research on the role of inflammation in HD.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Möller, T. Neuroinflammation in Huntington’s disease. J Neural Transm 117, 1001–1008 (2010). https://doi.org/10.1007/s00702-010-0430-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-010-0430-7