Top

Journal of Neuroinflammation

Published in:

Open Access 01-12-2017 | Research

Inhibition of colony-stimulating factor 1 receptor early in disease ameliorates motor deficits in SCA1 mice

Authors: Wenhui Qu, Andrea Johnson, Joo Hyun Kim, Abigail Lukowicz, Daniel Svedberg, Marija Cvetanovic

Published in: Journal of Neuroinflammation | Issue 1/2017

Abstract

Background

Polyglutamine (polyQ) expansion in the protein Ataxin-1 (ATXN1) causes spinocerebellar ataxia type 1 (SCA1), a fatal dominantly inherited neurodegenerative disease characterized by motor deficits, cerebellar neurodegeneration, and gliosis. Currently, there are no treatments available to delay or ameliorate SCA1. We have examined the effect of depleting microglia during the early stage of disease by using PLX, an inhibitor of colony-stimulating factor 1 receptor (CSFR1), on disease severity in a mouse model of SCA1.

Methods

Transgenic mouse model of SCA1, ATXN1[82Q] mice, and wild-type littermate controls were treated with PLX from 3 weeks of age. The effects of PLX on microglial density, astrogliosis, motor behavior, atrophy, and gene expression of Purkinje neurons were examined at 3 months of age.

Results

PLX treatment resulted in the elimination of 70–80% of microglia from the cerebellum of both wild-type and ATXN1[82Q] mice. Importantly, PLX ameliorated motor deficits in SCA1 mice. While we have not observed significant improvement in the atrophy or disease-associated gene expression changes in Purkinje neurons upon PLX treatment, we have detected reduced expression of pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) and increase in the protein levels of wild-type ataxin-1 and post-synaptic density protein 95 (PSD95) that may help improve PN function.

Conclusions

A decrease in the number of microglia during an early stage of disease resulted in the amelioration of motor deficits in SCA1 mice.

Available only for authorised users

Wang X, Chen S, Ma G, Ye M, Lu G. Involvement of proinflammatory factors, apoptosis, caspase-3 activation and Ca2+ disturbance in microglia activation-mediated dopaminergic cell degeneration. Mech Ageing Dev. 2005;126:1241–54.CrossRefPubMed

El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C, et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med. 2007;13:432–8. Available from: http://www.nature.com/nm/journal/v13/n4/full/nm1555.html.CrossRefPubMed

Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH, Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140:918–34. doi:10.1016/j.cell.2010.02.016.CrossRefPubMedPubMedCentral

Cvetanovic M, Ingram M, Orr H, Opal P. Early activation of microglia and astrocytes in mouse models of spinocerebellar ataxia type 1. Neuroscience. 2015;289:289–99. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0306452215000159.CrossRefPubMedPubMedCentral

Liao B, Zhao W, Beers DR, Henkel JS, Appel SH. Transformation from a neuroprotective to a neurotoxic microglial phenotype in a mouse model of ALS. Exp Neurol. 2012;237:147–52. doi:10.1016/j.expneurol.2012.06.011.CrossRefPubMedPubMedCentral

Platten M, Steinman L. Multiple sclerosis: trapped in deadly glue. Nat Med. 2005;11(3):252–3.CrossRefPubMed

Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med. 2000;6:797–801.CrossRefPubMed

Lian H, Yang L, Cole A, Sun L, Chiang AC, Fowler SW, et al. NFκB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer’s disease. Neuron. 2016;85:101–15.CrossRef

Ilieva H, Polymenidou M, Cleveland DW. Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J Cell Biol. 2009;187:761–72.CrossRefPubMedPubMedCentral

10.

Hong S, Dissing-Olesen L, Stevens B. New insights on the role of microglia in synaptic pruning in health and disease. Curr Opin Neurobiol. 2016;36:128–34. doi:10.1016/j.conb.2015.12.004.CrossRefPubMed

11.

Yuan P, Condello C, Keene CD, Wang Y, Bird TD, Paul SM, et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron. 2016;90:724–39. https://www.ncbi.nlm.nih.gov/pubmed/27196974.

12.

Aguzzi A, Barres BA, Bennett ML. Microglia: scapegoat, saboteur, or something else? Science (80-). 2013;339:156–61.CrossRef

13.

Stephan AH, Barres BA, Stevens B. The complement system: an unexpected role in synaptic pruning during development and disease. Annu Rev Neurosci. 2012;35:369–89.CrossRefPubMed

14.

Guo Z, Iyun T, Fu W, Zhang P, Mattson MP. Bone marrow transplantation reveals roles for brain macrophage/microglia TNF signaling and nitric oxide production in excitotoxic neuronal death. Neuromolecular Med. 2004;5:219–34.CrossRefPubMed

15.

Harry GJ. Microglia during development and aging. Pharmacol Ther. 2013;139:313–26. doi:10.1016/j.pharmthera.2013.04.013.CrossRefPubMedPubMedCentral

16.

McGeer PL, McGeer EG. History of innate immunity in neurodegenerative disorders. Front Pharmacol. 2011;2:1–5.CrossRef

17.

Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo—resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. 2005;308:1314–9. http://science.sciencemag.org/content/308/5726/1314.long.

18.

Boillée S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science. 2006;312:1389–92.CrossRefPubMed

19.

Tong X, Ao Y, Faas GC, Nwaobi SE, Xu J, Haustein MD, et al. Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington’s disease model mice. Nat. Neurosci. 2014;17:694–703. https://www.nature.com/neuro/journal/v17/n5/full/nn.3691.html.

20.

Crotti A, Benner C, Kerman BE, Gosselin D, Lagier-Tourenne C, Zuccato C, et al. Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors. Nat Neurosci. 2014;17:513–21. doi:10.1038/nn.3668.CrossRefPubMedPubMedCentral

21.

McGeer PL, McGeer EG. Glial reactions in Parkinson’s disease. Mov Disord. 2008;23:474–83.CrossRefPubMed

22.

Gerhard A, Pavese N, Hotton G, Turkheimer F, Es M, Hammers A, et al. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol Dis. 2006;21:404–12.CrossRefPubMed

23.

Politis M, Lahiri N, Niccolini F, Su P, Wu K, Giannetti P, et al. Increased central microglial activation associated with peripheral cytokine levels in premanifest Huntington’s disease gene carriers. Neurobiol Dis. 2015;83:115–21. doi:10.1016/j.nbd.2015.08.011.CrossRefPubMed

24.

Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR, Lafaille JJ, et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell. 2013;155:1596–609.CrossRefPubMedPubMedCentral

25.

Beers DR, Henkel JS, Xiao Q, Zhao W, Wang J, Yen AA, et al. Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2006;103:16021–6. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1613228&tool=pmcentrez&rendertype=abstract.

26.

Ginhoux F, Lim S, Hoeffel G, Low D, Huber T. Origin and differentiation of microglia. Front Cell Neurosci. 2013;7:45. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627983/.

27.

Gowing G, Philips T, Van Wijmeersch B, Audet J-N, Dewil M, Van Den Bosch L, et al. Ablation of proliferating microglia does not affect motor neuron degeneration in amyotrophic lateral sclerosis caused by mutant superoxide dismutase. J Neurosci. 2008;28:10234–44. Available from: http://www.jneurosci.org/content/28/41/10234.long.CrossRefPubMed

28.

Streit WJ. Microglia as neuroprotective, immunocompetent cells of the CNS. Glia. 2002;40:133–9.CrossRefPubMed

29.

Artegiani B, Lindemann D, Calegari F. Overexpression of cdk4 and cyclinD1 triggers greater expansion of neural stem cells in the adult mouse brain. J Exp Med. 2011;208:937–48. Available from: http://jem.rupress.org/content/208/5/937.short.CrossRefPubMedPubMedCentral

30.

31.

Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, et al. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature [Internet]. Nat Publ Group. 2016;540:230–5. doi:10.1038/nature20587.

32.

Bürk K, Globas C, Bösch S, Klockgether T, Zühlke C, Daum I, et al. Cognitive deficits in spinocerebellar ataxia type 1, 2, and 3. J Neurol. 2003;250:207–11.CrossRefPubMed

33.

Zoghbi HY, Orr HT. Pathogenic mechanisms of a polyglutamine-mediated neurodegenerative disease, Spinocerebellar ataxia type 1. J Biol Chem. 2009;284:7425–9.CrossRefPubMedPubMedCentral

34.

Banfi S, Servadio A, Chung M, Kwiatkowski TJ, McCall AE, Duvick LA, et al. Identification and characterization of the gene causing type 1 spinocerebellar ataxia. Nat Genet. 1994;7:513–20. doi:10.1038/ng0894-513.CrossRefPubMed

35.

Banfi S, Servadio A, Chung M, Capozzoli F, Duvick LA, Elde R, et al. Cloning and developmental expression analysis of the murine homolog of the spinocerebellar ataxia type 1 gene (Sca1). Hum Mol Genet. 1996;5:33–40.CrossRefPubMed

36.

Matilla-Dueñas A, Goold R, Giunti P. Clinical, genetic, molecular, and pathophysiological insights into spinocerebellar ataxia type 1. Cerebellum. 2008;7:106–14. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18418661.CrossRefPubMed

37.

Oz G, Hutter D, Tkác I, Clark HB, Gross MD, Jiang H, et al. Neurochemical alterations in spinocerebellar ataxia type 1 and their correlations with clinical status. Mov Disord. 2010;25:1253–61.CrossRefPubMedPubMedCentral

38.

Renee M, Elmore P, Najafi AR, Koike MA, Nazih N, Spangenberg EE, et al. CSF1 receptor signaling is necessary for microglia viability, which unmasks a cell that rapidly repopulates the microglia- depleted adult brain. Neuron. 2015;82:380–97.

39.

Bañez-Coronel M, Ayhan F, Tarabochia AD, Zu T, Perez BA, Tusi SK, et al. RAN translation in Huntington disease. Neuron. 2015;88:667–77. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26590344.CrossRefPubMedPubMedCentral

40.

Duvick L, Barnes J, Ebner B, Agrawal S, Andresen M, Lim J, et al. SCA1-like disease in mice expressing wild-type Ataxin-1 with a serine to aspartic acid replacement at residue 776. Neuron. 2010;67:929–35. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20869591.

41.

Cvetanovic M, Patel JM, Marti HH, Kini AR, Opal P. Vascular endothelial growth factor ameliorates the ataxic phenotype in a mouse model of spinocerebellar ataxia type 1. Nat. Med. 2011. 1445–7.

42.

Burright EN, Clark HB, Servadio A, Matilla T, Feddersen RM, Yunis WS, et al. SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell. 1995;82:937–48.CrossRefPubMed

43.

Cvetanovic M, Patel JM, Marti HH, Kini AR, Opal P. Vascular endothelial growth factor ameliorates the ataxic phenotype in a mouse model of spinocerebellar ataxia type 1. Nat Med. 2011;17:1445–7.CrossRefPubMedPubMedCentral

44.

Hothorn T, Hornik K, van de Wiel M, Zeileis A. Implementing a class of permutation tests: the coin package. J Stat Softw. 2008;28:1–23.CrossRef

45.

Magniafico S. Functions to Support Extension Education Program Evaluation Package “rcompanion.” CRAN. 2016. https://rdrr.io/cran/rcompanion/.

46.

Ingram M, Wozniak EAL, Duvick L, Yang R, Bergmann P, Carson R, et al. Cerebellar transcriptome profiles of ATXN1 transgenic mice reveal SCA1 disease progression and protection pathways. Neuron. 2016;89:1194-207. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795980/.

47.

Cvetanovic M. Decreased expression of glutamate transporter GLAST in bergmann glia is associated with the loss of Purkinje neurons in the spinocerebellar ataxia type 1. Cerebellum. 2015;14:8–11.CrossRefPubMed

48.

Pekny M, Pekna M, Messing A, Steinhäuser C, Lee JM, Parpura V, Hol EM, Sofroniew MV, Verkhratsky A. Astrocytes: a central element in neurological diseases. Acta Neuropathol. 2016;131:323–45.CrossRefPubMed

49.

Watase K, Weeber EJ, Xu B, Antalffy B, Yuva-Paylor L, Hashimoto K, et al. A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration. Neuron. 2002;34:905–19.CrossRefPubMed

50.

Barnes JA, Ebner BA, Duvick LA, Gao W, Chen G, Orr HT, et al. Abnormalities in the climbing fiber-Purkinje cell circuitry contribute to neuronal dysfunction in ATXN1[82Q] mice. J Neurosci. 2011;31:12778–89. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3178465&tool=pmcentrez&rendertype=abstract.CrossRefPubMedPubMedCentral

51.

Cvetanovic M, Kular RK, Opal P. LANP mediates neuritic pathology in Spinocerebellar ataxia type 1. Neurobiol Dis. 2012;48:526–32.CrossRefPubMedPubMedCentral

52.

Lim J, Crespo-Barreto J, Jafar-Nejad P, Bowman AB, Richman R, Hill DE, et al. Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature. 2008;452:713–8. Available from: https://www.nature.com/nature/journal/v452/n7188/full/nature06731.html.CrossRefPubMedPubMedCentral

53.

Bennetta ML, Bennetta C, Liddelowa SA, Ajami B, Zamanian JL, Fernhoff NB, et al. New tools for studying microglia in the mouse and human CNS. Pnas [Internet]. 2016;1525528113-. Available from: http://www.pnas.org/content/early/2016/02/10/1525528113.abstract

54.

Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE, Shaked GM, et al. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nat Med. 2009;15:331–7. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2838375&tool=pmcentrez&rendertype=abstract.

55.

Hanisch U-KK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat. Neurosci. 2007;10:1387–94. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17965659.

56.

Graeber MB, Streit WJ. Microglia: biology and pathology. Acta Neuropathol. 2010;119:89–105.CrossRefPubMed

57.

Hickman SE, Kingery ND, Ohsumi T, Borowsky M, Means TK, El Khoury J. The microglial sensome revealed by direct RNA sequencing. Nat Neurosci. 2013;16:1896–905.CrossRefPubMedPubMedCentral

58.

Mathis C, Collin L, Borrelli E. Oligodendrocyte ablation impairs cerebellum development. Development [Internet]. 2003;130:4709–18. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12925596

59.

Káradóttir R, Cavelier P, Bergersen LH, Attwell D. NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature. 2005;438:1162–6. https://www.nature.com/nature/journal/v438/n7071/full/nature04302.html.

60.

Kassmann CM, Lappe-Siefke C, Baes M, Brügger B, Mildner A, Werner HB, et al. Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes. Nat. Genet. [Internet]. 2007;39:969–76. Available from: http://www.nature.com/doifinder/10.1038/ng2070

61.

Lin W, Lin Y, Li J, Fenstermaker AG, Way SW, Clayton B, et al. Oligodendrocyte-specific activation of PERK signaling protects mice against experimental autoimmune encephalomyelitis. J Neurosci. 2013;33:5980–91. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3654380&tool=pmcentrez&rendertype=abstract.CrossRefPubMedPubMedCentral

Title: Inhibition of colony-stimulating factor 1 receptor early in disease ameliorates motor deficits in SCA1 mice
Authors: Wenhui Qu
Andrea Johnson
Joo Hyun Kim
Abigail Lukowicz
Daniel Svedberg
Marija Cvetanovic
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2017
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-017-0880-z

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Inhibition of colony-stimulating factor 1 receptor early in disease ameliorates motor deficits in SCA1 mice

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2017

Lentivirus-mediated interleukin-1β (IL-1β) knock-down in the hippocampus alleviates lipopolysaccharide (LPS)-induced memory deficits and anxiety- and depression-like behaviors in mice

Neuroinflammation contributes to autophagy flux blockage in the neurons of rostral ventrolateral medulla in stress-induced hypertension rats

Tissue transglutaminase in astrocytes is enhanced by inflammatory mediators and is involved in the formation of fibronectin fibril-like structures

Dimethylarginines in patients with intracerebral hemorrhage: association with outcome, hematoma enlargement, and edema

DNA repair protein APE1 is involved in host response during pneumococcal meningitis and its expression can be modulated by vitamin B6

Pathophysiology of chronic subdural haematoma: inflammation, angiogenesis and implications for pharmacotherapy