[en] Chemokines are important modulators of neuroinflammation and neurodegeneration. In the brains of Alzheimer's disease (AD) patients and in AD animal models, the chemokine CXCL10 is found in high concentrations, suggesting a pathogenic role for this chemokine and its receptor, CXCR3. Recent studies aimed at addressing the role of CXCR3 in neurological diseases indicate potent, but diverse, functions for CXCR3. Here, we examined the impact of CXCR3 in the amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD. We found that, compared with control APP/PSI animals, plaque burden and Aβ levels were strongly reduced in CXCR3-deficient APP/PS1 mice. Analysis of microglial phagocytosis in vitro and in vivo demonstrated that CXCR3 deficiency increased the microglial uptake of Aβ. Application of a CXCR3 antagonist increased microglial Aβ phagocytosis, which was associated with reduced TNF-α secretion. Moreover, in CXCR3-deficient APP/PS1 mice, microglia exhibited morphological activation and reduced plaque association, and brain tissue from APP/PS1 animals lacking CXCR3 had reduced concentrations of proinflammatory cytokines compared with controls. Further, loss of CXCR3 attenuated the behavioral deficits observed in APP/PS1 mice. Together, our data indicate that CXCR3 signaling mediates development of AD-like pathology in APP/PS1 mice and suggest that CXCR3 has potential as a therapeutic target for AD.
Disciplines :
Neurology
Author, co-author :
Krauthausen, Marius; Department of Neurology, Universitätsklinikum Bonn, Bonn, Germany
Kummer, Markus P; Department of Neurology, Universitätsklinikum Bonn, Bonn, Germany
Zimmermann, Julian; Department of Neurology, Universitätsklinikum Bonn, Bonn, Germany
Reyes-Irisarri, Elisabet; Department of Neurology, Universitätsklinikum Bonn, Bonn, Germany
Terwel, Dick; Department of Neurology, Universitätsklinikum Bonn, Bonn, Germany
Bulic, Bruno; Laboratory of Organic Synthesis of Functional Systems, Humboldt-Universität zu Berlin, Berlin, Germany
HENEKA, Michael ; Department of Neurology, Universitätsklinikum Bonn, Bonn, Germany
Müller, Marcus; Department of Neurology, Universitätsklinikum Bonn, Bonn, Germany
External co-authors :
yes
Language :
English
Title :
CXCR3 promotes plaque formation and behavioral deficits in an Alzheimer's disease model.
Publication date :
January 2015
Journal title :
Journal of Clinical Investigation
ISSN :
0021-9738
eISSN :
1558-8238
Publisher :
American Society for Clinical Investigation, United States
Parpura V, et al. Glial cells in (patho)physiology. J Neurochem. 2012;121(1):4-27.
Perry VH, Gordon S. Macrophages and microg-lia in the nervous system. Trends Neurosci. 1988;11(6):273-277.
Lawson LJ, Perry VH, Gordon S. Turnover of resident microglia in the normal adult mouse brain. Neuroscience. 1992;48(2):405-415.
Koenigsknecht-Talboo J, Landreth GE. Microglial phagocytosis induced by fibrillar β-amyloid and IgGs are differentially regulated by proinflamma-tory cytokines. J Neurosci. 2005;25(36):8240-8249.
Shie F-S, Breyer RM, Montine TJ. Microglia lacking E Prostanoid Receptor subtype 2 have enhanced Aβ phagocytosis yet lack Aβ-activated neurotoxic-ity. Am J Pathol. 2005;166(4):1163-1172.
Yamamoto M, et al. Overexpression of mono-cyte chemotactic protein-1/CCL2 in β-amyloid precursor protein transgenic mice show accelerated diffuse β-amyloid deposition. Am J Pathol. 2005;166(5):1475-1485.
Town T, et al. Blocking TGF-[beta]-Smad2/3 innate immune signaling mitigates Alzheimerlike pathology. Nat Med. 2008;14(6):681-687.
Krause DL, Müller N. Neuroinflammation, microglia and implications for anti-inflammatory treatment in Alzheimer's disease. Int J Alzheimer Dis. 2010;2010:732806.
Reed-Geaghan EG, Reed QW, Cramer PE, Landreth GE. Deletion of CD14 attenuates Alzheimer's disease pathology by influencing the brain's inflammatory milieu. J Neurosci. 2010;30(46):15369-15373.
Heneka MT, et al. NLRP3 is activated in Alzheimer/'s disease and contributes to pathology in APP/PS1 mice. Nature. 2013;493(7434):674-678.
Wyss-Coray T, Mucke L. Inflammation in neuro-degenerative disease - a double-edged sword. Neuron. 2002;35(3):419-432.
Paresce D, Ghosh R, Maxfield F. Microglial cells internalize aggregates of the Alzheimer's disease Amyloid β-protein via a scavenger receptor. Neuron. 1996;17(3):553-565.
Weldon DT, et al. Fibrillar β-amyloid induces microglial phagocytosis, expression of inducible nitric oxide synthase, and loss of a select population of neurons in the rat CNS in vivo. J Neurosci. 1998;18(6):2161-2173.
Koenigsknecht J, Landreth G. Microglial phagocytosis of fibrillar β-amyloid through a β1 integrin-dependent mechanism. J Neurosci. 2004;24(44):9838-9846.
Charo IF, Ransohoff RM. The many roles of che-mokines and chemokine receptors in inflammation. N Engl J Med. 2006;354(6):610-621.
Müller M, Carter S, Hofer MJ, Campbell IL. Review: The chemokine receptor CXCR3 and its ligands CXCL9, CXCL10 and CXCL11 in neu-roimmunity - a tale of conflict and conundrum. Neuropathol Appl Neurobiol. 2010;36(5):368-387.
Loetscher M, et al. Chemokine receptor specific for IP10 and mig: structure, function, and expression in activated T-lymphocytes. J Exp Med. 1996;184(3):963-969.
Weng Y, et al. Binding and functional properties of recombinant and endogenous CXCR3 chemokine receptors. J Biol Chem. 1998;273(29):18288-18291.
Sallusto F, Lanzavecchia A. Understanding dendritic cell and T-lymphocyte traffic through the analysis of chemokine receptor expression. Immunol Rev. 2000;177:134-140.
Biber K, et al. Functional expression of CXCR3 in cultured mouse and human astrocytes and microglia. Neuroscience. 2002;112(3):487-497.
Flynn G. Regulation of chemokine receptor expression in human microglia and astrocytes. J Neuroimmunol. 2003;136(1-2):84-93.
Rappert A, et al. CXCR3-dependent microglial recruitment is essential for dendrite loss after brain lesion. J Neurosci. 2004;24(39):8500-8509.
De Jong EK, et al. Expression of CXCL4 in microglia in vitro and in vivo and its possible signaling through CXCR3. J Neurochem. 2008;105(5):1726-1736.
Xia MQ, Bacskai BJ, Knowles RB, Qin SX, Hyman BT. Expression of the chemokine receptor CXCR3 on neurons and the elevated expression of its ligand IP-10 in reactive astrocytes: in vitro ERK1/2 activation and role in Alzheimer's disease. J Neuroimmunol. 2000;108(1-2):227-235.
Nelson TE, Gruol DL. The chemokine CXCL10 modulates excitatory activity and intracellular calcium signaling in cultured hippocampal neurons. J Neuroimmunol. 2004;156(1-2):74-87.
Zhang B, Patel J, Croyle M, Diamond MS, Klein RS. TNF-alpha-dependent regulation of CXCR3 expression modulates neuronal survival during West Nile virus encephalitis. J Neuroimmunol. 2010;224(1-2):28-38.
Loetscher M, Loetscher P, Brass N, Meese E, Moser B. Lymphocyte-specific chemokine receptor CXCR3: regulation, chemokine binding and gene localization. Eur J Immunol. 1998;28(11):3696-3705.
Luster AD, Unkeless JC, Ravetch JV. y-Interferon transcriptionally regulates an early-response gene containing homology to platelet proteins. Nature. 1985;315(6021):672-676.
Cole KE, et al. Interferon-inducible T cell a che-moattractant (I-TAC): a novel non-ELR CXC che-mokine with potent activity on activated T cells through selective high affinity binding to CXCR3. J Exp Med. 1998;187(12):2009-2021.
Carter SL, Müller M, Manders PM, Campbell IL. Induction of the genes for Cxcl9 and Cxcl10 is dependent on IFN-y but shows differential cellular expression in experimental autoimmune encephalomyelitis and by astrocytes and microglia in vitro. Glia. 2007;55(16):1728-1739.
Zhang B, Patel J, Croyle M, Diamond MS, Klein RS. TNF-alpha-dependent regulation of CXCR3 expression modulates neuronal survival during West Nile virus encephalitis. J Neuroimmunol. 2010;2 24(1-2):28-38.
Choi K, Ni L, Jonakait GM. Fas ligation and tumor necrosis factor alpha activation of murine astrocytes promote heat shock factor-1 activation and heat shock protein expression leading to che-mokine induction and cell survival. J Neurochem. 2011;116(3):438-448.
Lee YK, et al. CCR5 deficiency induces astrocyte activation, Abeta deposit and impaired memory function. Neurobiol Learn Mem. 2009; 92(3): 356-363.
El Khoury J, et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med. 2007;13(4):432-438.
Kiyota T, et al. CCL2 accelerates microglia-mediated Aß oligomer formation and progression of neurocognitive dysfunction. PLoS One. 2009;4(7):e6197
Semple BD, Frugier T, Morganti-Kossmann MC. CCL2 modulates cytokine production in cultured mouse astrocytes. J Neuroinflammation. 2010;7:67.
Fuhrmann M, et al. Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease. Nat Neurosci. 2010;13(4):411-413.
Lee S, et al. CX3CR1 deficiency alters microglial activation and reduces ß-amyloid deposition in two Alzheimer's disease mouse models. Am J Pathol. 2010;177(5):2549-2562.
Liu Z, Condello C, Schain A, Harb R, Grut-zendler J. CX3CR1 in microglia regulates brain amyloid deposition through selective proto-fibrillar amyloid-ß phagocytosis. J Neurosci. 2010;30(50):17091-17101.
Nash KR, et al. Fractalkine overexpression suppresses tau pathology in a mouse model of tauop-athy. Neurobiol Aging. 2013;34(6):1540-1548.
Galimberti D, Schoonenboom N, Scarpini E, Scheltens P. Chemokines in serum and cerebrospinal fluid of Alzheimer's disease patients. Ann Neurol. 2003;53(4):547-548.
Galimberti D, et al. Intrathecal chemokine synthesis in mild cognitive impairment and Alzheimer disease. Arch Neurol. 2006;63(4):538-543.
Duan R-S, et al. Decreased fractalkine and increased IP-10 expression in aged brain of APP(swe) transgenic mice. Neurochem Res. 2008;33(6):1085-1089.
Jankowsky JL, et al. Mutant presenilins specifically elevate the levels of the 42 residue ß-amyloid peptide in vivo: evidence for augmentation of a 42-specificy secretase. Hum Mol Genet. 2004;13(2):159-170.
Garcia-Alloza M, et al. Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease. Neurobiol Dis. 2006;24(3):516-524.
Ruan L, Kang Z, Pei G, Le Y. Amyloid deposition and inflammation in APPswe/PS1dE9 mouse model of Alzheimer's disease. Curr Alzheimer Res. 2009;6(6):531-540.
Hammerschmidt T, et al. Selective loss of noradrenaline exacerbates early cognitive dysfunction and synaptic deficits in APP/PS1 mice. Biol Psychiatry. 2013;73(5):454-463.
Jankowsky JL, et al. Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng. 2001;17(6):157-165.
Cho J, Nelson TE, Bajova H, Gruol DL. Chronic CXCL10 alters neuronal properties in rat hippocampal culture. J Neuroimmunol. 2 009;207(1-2): 92-100.
Sui Y, et al. CXCL10-induced cell death in neurons: role of calcium dysregulation. Eur J Neuro-sci. 2006;23(4):957-964.
Coughlan CM, et al. Expression of multiple functional chemokine receptors and monocyte chemoattractant protein-1 in human neurons. Neuroscience. 2000;97(3) 591-600.
Riemer C, et al. Accelerated prion replication in, but prolonged survival times of, prion-infected CXCR3-/-mice. J Virol. 2008;82(24):12464-12471.
Koistinaho M, et al. Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-ß peptides. Nat Med. 2004;10(7):719-726.
Farina C, Aloisi F, Meinl E. Astrocytes are active players in cerebral innate immunity. Trends Immunol. 2007;28(3):138-145.
Van Weering HRJ, et al. CXCL10/CXCR3 signaling in glia cells differentially affects NMDA-induced cell death in CA and DG neurons of the mouse hippocampus. Hippocampus. 2 011;21(2):2 2 0-2 3 2.
Amor S, Puentes F, Baker D, van der Valk P. Inflammation in neurodegenerative diseases. Immunology. 2010;129(2):154-169.
Ramos EM, et al. Tumor necrosis factor a and interleukin 10 promoter region polymorphisms and risk of late-onset Alzheimer disease. Arch Neurol. 2006;63(8):1165-1169.
Tobinick E, Gross H, Weinberger A, Cohen H. TNF-α modulation for treatment of Alzheimer's disease: a 6-month pilot study. Med Gen Med. 2006;8(2):25.
Pardridge WM. Biologic TNFα-inhibitors that cross the human blood-brain barrier. Bioeng Bugs. 2010;1(4):231-234.
Frankola KA, Greig NH, Luo W, Tweedie D. Targeting TNF-α to elucidate and ameliorate neuroinflammation in neurodegenerative diseases. CNS Neurol Disord Drug Targets. 2011;10(3):391-403.
McAlpine FE, et al. Inhibition of soluble TNF signaling in a mouse model of Alzheimer's disease prevents pre-plaque amyloid-associated neuro-pathology. Neurobiol Dis. 2009;34(1):163-177.
Hofmann K, Tschopp J. The death domain motif found in Fas (Apo-1) and TNF receptor is present in proteins involved in apoptosis and axonal guidance. FEBS Lett. 1995;371(3):321-323.
Felderhoff-Mueser U, et al. Fas/CD95/APO-1 can function as a death receptor for neuronal cells in vitro and in vivo and is upregulated following cerebral hypoxic-ischemic injury to the developing rat brain. Brain Pathol. 2000;10(1):17-29.
Ethell DW, Buhler LA. Fas ligand-mediated apop-tosis in degenerative disorders of the brain. J Clin Immunol. 2003;23(6):439-446.
Su JH, et al. Fas and Fas ligand are associated with neuritic degeneration in the AD brain and participate in β-amyloid-induced neuronal death. Neurobiol Dis. 2003;12(3):182-193.
Pinteaux E, Trotter P, Simi A. Cell-specific and concentration-dependent actions of interleu-kin-1 in acute brain inflammation. Cytokine. 2009;45(1):1-7.
Müller M, et al. CXCR3 signaling reduces the severity of experimental autoimmune encephalomyelitis by controlling the parenchy-mal distribution of effector and regulatory T cells in the central nervous system. J Immunol. 2007;179(5):2774-2786.
Miu J, et al. Chemokine gene expression during fatal murine cerebral malaria and protection due to CXCR3 deficiency. J Immunol. 2008;180(2):1217-1230.
Christensen JE, et al. Efficient T-cell surveillance of the CNS requires expression of the CXC chemokine receptor 3. J Neurosci. 2004;24(20):4849-4858.
Zhang W, Wang PJ, Sha HY, Ni J, Li MH, Gu GJ. Neural stem cell transplants improve cognitive function without altering amyloid pathology in an APP/PS1 double transgenic model of Alzheimer's disease. Mol Neurobiol. 2014;50(2):423-437.
Nagahara AH, et al. Early BDNF treatment ameliorates cell loss in the entorhinal cortex of APP trans-genic mice. J Neurosci. 2013;33(39):15596-15602.
Klegeris A, Walker DG, McGeer PL. Interaction of Alzheimer β-amyloid peptide with the human monocytic cell line THP-1 results in a protein kinase C-dependent secretion of tumor necrosis factor-alpha. Brain Res. 1997;747(1):114-121.
Gregersen R, Lambertsen K, Finsen B. Microglia and macrophages are the major source of tumor necrosis factor in permanent middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab. 2000;20(1):53-65.
Lue LF, et al. Inflammatory repertoire of Alzheimer's disease and nondemented elderly microglia in vitro. Glia. 2001;35(1):72-79.
Hanisch U-K. Microglia as a source and target of cytokines. Glia. 2002;40(2):140-155.
Ferber I, et al. Mice with a disrupted IFN-y gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J Immunol. 1996;156(1):5-7
Majumder S, et al. Regulation of human IP-10 gene expression in astrocytoma cells by inflammatory cytokines. J Neurosci Res. 1998;54(2):169-180.
Smit MJ, Lira SA, Leurs R. Chemokine Receptors as Drug Targets. Malden, Massachusetts, USA: John Wiley & Sons; 2010.
Krauthausen M, et al. Opposing roles for CXCR3 signaling in central nervous system versus ocular inflammation mediated by the astrocyte-targeted production of IL-12. Am J Pathol. 2011;179(5):2346-2359.
Hancock WW, et al. Requirement of the chemokine receptor CXCR3 for acute allograft rejection. J Exp Med. 2000;192(10):1515-1520.
Candore G, et al. Age-related inflammatory diseases: role of genetics and gender in the pathophysiology of Alzheimer's disease. Ann N Y Acad Sci. 2006;1089:472-486.
Casadesus G, et al. The estrogen myth: potential use of gonadotropin-releasing hormone agonists for the treatment of Alzheimer's disease. Drugs R D. 2006;7(3):187-193.
Müller M, Wacker K, Getts D, Ringelstein EB, Kiefer R. Further evidence for a crucial role of resident endoneurial macrophages in peripheral nerve disorders: Lessons from acrylamide-induced neuropathy. Glia. 2008;56(9):1005-1016.
Martin LJ, et al. Amyloid precursor protein in aged nonhuman primates. Proc Natl Acad Sci U S A. 1991;88(4):1461-1465.
Hanisch U-K, et al. The microglia-acti-vating potential of thrombin. J Biol Chem. 2004;279(50):51880-51887.
Teplow DB. Preparation of amyloid beta-protein for structural and functional studies. Meth Enzy-mol. 2006;413:20-33.
Fleisher-Berkovich S, et al. Distinct modulation of microglial amyloid ß phagocytosis and migration by neuropeptides (i). J Neuroinflammation. 2010;7:61.
Hayes ME, et al. Discovery of small molecule benzimidazole antagonists of the chemokine receptor CXCR3. Bioorg Medicinal Chem Lett. 2008;18(5):1573-1576.
Kummer MP, et al. Nitration of tyrosine 10 critically enhances amyloid ß aggregation and plaque formation. Neuron. 2011;71(5):833-844.
Jäger S, et al. a-secretase mediated conversion of the amyloid precursor protein derived membrane stub C99 to C8 3 limits Aß generation. J Neuro-chem. 2009;111(6):1369-1382.
