Abstract
A recent study suggested that neuroinflammation plays a major role in the pathogenesis of a number of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Although the precise mechanism is obscure, dysregulation of the signaling transduction pathway in microglia may enhance inflammation, leading to synaptic dysfunction and ultimately to neuronal cell death. The expression and function of the P2X7 receptor (P2X7R), an ATP-gated ion channel abundantly expressed in microglia in the brain, is significantly up-regulated in the postmortem brain of Alzheimer’s disease patients and various neurodegenerative disease animal models. This supports the role of the P2X7R pathway in the progression of neurodegeneration. Blocking P2X7R using brilliant blue G, a P2X7R antagonist that can cross the blood–brain barrier, has been shown to result in the amelioration of neuropathology in various animal models. Taken together, these results raise the possibility that the P2X7R signaling pathway could be a therapeutic target for treating various neurodegenerative diseases.
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Abbreviations
- AD:
-
Alzheimer’s disease
- P2X7R:
-
P2X7 receptor
- Aβ:
-
Amyloid-β
- CNS:
-
Central nervous system
- IL-1β:
-
Interleukin-1β
- PrPSc :
-
Infectious form of prion protein
- HD:
-
Huntington’s disease
- BBG:
-
Brilliant blue G
References
Abbracchio MP, Burnstock G, Boeynaems JM et al (2006) International Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy. Pharmacol Rev 58:281–341
Anderson CM, Nedergaard M (2006) Emerging challenges of assigning P2X7 receptor function and immunoreactivity in neurons. Trends Neurosci 29:257–262
Bianco F, Ceruti S, Colombo A et al (2006) A role for P2X7 in microglial proliferation. J Neurochem 99:745–758
Borzelleca JF, Depukat K, Hallagan JB (1990) Lifetime toxicity/carcinogenicity studies of FD & C Blue No. 1 (brilliant blue FCF) in rats and mice. Food Chem Toxicol 28:221–234
Crozet C, Beranger F, Lehmann S (2008) Cellular pathogenesis in prion diseases. Vet Res 39:44
Denlinger LC, Fisette PL, Sommer JA et al (2001) Cutting edge: the nucleotide receptor P2X7 contains multiple protein- and lipid-interaction motifs including a potential binding site for bacterial lipopolysaccharide. J Immunol 167:1871–1876
Di Virgilio F, Chiozzi P, Falzoni S et al (1998) Cytolytic P2X purinoceptors. Cell Death Differ 5:191–199
Diaz-Hernandez M, Diez-Zaera M, Sanchez-Nogueiro J et al (2009) Altered P2X7-receptor level and function in mouse models of Huntington’s disease and therapeutic efficacy of antagonist administration. FASEB J 23:1893–1906
Duan S, Neary JT (2006) P2X(7) receptors: properties and relevance to CNS function. Glia 54:738–746
Duan S, Anderson CM, Keung EC et al (2003) P2X7 receptor-mediated release of excitatory amino acids from astrocytes. J Neurosci 23:1320–1328
Ferrari D, Villalba M, Chiozzi P et al (1996) Mouse microglial cells express a plasma membrane pore gated by extracellular ATP. J Immunol 156:1531–1539
Ferrari D, Chiozzi P, Falzoni S et al (1997a) ATP-mediated cytotoxicity in microglial cells. Neuropharmacology 36:1295–1301
Ferrari D, Chiozzi P, Falzoni S et al (1997b) Purinergic modulation of interleukin-1β release from microglial cells stimulated with bacterial endotoxin. J Exp Med 185:579–582
Ferrari D, Wesselborg S, Bauer MK et al (1997c) Extracellular ATP activates transcription factor NF-κB through the P2Z purinoreceptor by selectively targeting NF-κB p65. J Cell Biol 139:1635–1643
Ferrari D, Pizzirani C, Adinolfi E et al (2006) The P2X7 receptor: a key player in IL-1 processing and release. J Immunol 176:3877–3883
Fujita M, Wei J, Nakai M et al (2006) Chaperone and anti-chaperone: two-faced synuclein as stimulator of synaptic evolution. Neuropathology 26:383–392
Garden GA, Moller T (2006) Microglia biology in health and disease. J Neuroimmune Pharmacol 1:127–137
Gendron FP, Chalimoniuk M, Strosznajder J et al (2003) P2X7 nucleotide receptor activation enhances IFNγ-induced type II nitric oxide synthase activity in BV-2 microglial cells. J Neurochem 87:344–352
Hashimoto M, Masliah E (1999) α-synuclein in Lewy body disease and Alzheimer’s disease. Brain Pathol 9:707–720
Hess SM, Fitzhugh OG (1955) Absorption and excretion of certain triphenylmethane colors in rats and dogs. J Pharmacol Exp Ther 114:38–42
Iwamaru Y, Takenouchi T, Ogihara K et al (2007) Microglial cell line established from prion protein-overexpressing mice is susceptible to various murine prion strains. J Virol 81:1524–1527
Jiang LH (2009) Inhibition of P2X(7) receptors by divalent cations: old action and new insight. Eur Biophys J 38:339–346
Jimenez S, Baglietto-Vargas D, Caballero C 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 28:11650–11661
Kataoka A, Tozaki-Saitoh H, Koga Y et al (2009) Activation of P2X7 receptors induces CCL3 production in microglial cells through transcription factor NFAT. J Neurochem 108:115–125
Kaur C, Hao AJ, Wu CH et al (2001) Origin of microglia. Microsc Res Tech 54:2–9
Langston JW, Ballard P, Tetrud JW et al (1983) Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:979–980
Matute C, Torre I, Perez-Cerda F et al (2007) P2X(7) receptor blockade prevents ATP excitotoxicity in oligodendrocytes and ameliorates experimental autoimmune encephalomyelitis. J Neurosci 27:9525–9533
McLarnon JG, Ryu JK, Walker DG et al (2006) Upregulated expression of purinergic P2X(7) receptor in Alzheimer disease and amyloid-beta peptide-treated microglia and in peptide-injected rat hippocampus. J Neuropathol Exp Neurol 65:1090–1097
Monif M, Reid CA, Powell KL et al (2009) The P2X7 receptor drives microglial activation and proliferation: a trophic role for P2X7R pore. J Neurosci 29:3781–3791
Norenberg W, Illes P (2000) Neuronal P2X receptors: localisation and functional properties. Naunyn Schmiedebergs Arch Pharmacol 362:324–339
North RA (2002) Molecular physiology of P2X receptors. Physiol Rev 82:1013–1067
Parvathenani LK, Tertyshnikova S, Greco CR et al (2003) P2X7 mediates superoxide production in primary microglia and is up-regulated in a transgenic mouse model of Alzheimer’s disease. J Biol Chem 278:13309–13317
Peng W, Cotrina ML, Han X et al (2009) Systemic administration of an antagonist of the ATP-sensitive receptor P2X7 improves recovery after spinal cord injury. Proc Natl Acad Sci USA 106:12489–12493
Prusiner SB (1991) Molecular biology of prion diseases. Science 252:1515–1522
Ryu JK, McLarnon JG (2008) Block of purinergic P2X(7) receptor is neuroprotective in an animal model of Alzheimer’s disease. Neuroreport 19:1715–1719
Sanz JM, Chiozzi P, Ferrari D et al (2009) Activation of microglia by amyloid β requires P2X7 receptor expression. J Immunol 182:4378–4385
Selkoe DJ (1996) Amyloid β-protein and the genetics of Alzheimer’s disease. J Biol Chem 271:18295–18298
Sim JA, Young MT, Sung HY et al (2004) Reanalysis of P2X7 receptor expression in rodent brain. J Neurosci 24:6307–6314
Sugama S, Yang L, Cho BP et al (2003) Age-related microglial activation in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration in C57BL/6 mice. Brain Res 964:288–294
Sugama S, Takenouchi T, Cho BP et al (2009) Possible roles of microglial cells for neurotoxicity in clinical neurodegenerative diseases and experimental animal models. Inflamm Allergy Drug Targets 8:277–284
Surprenant A, Rassendren F, Kawashima E et al (1996) The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7). Science 272:735–738
Suzuki T, Hide I, Ido K et al (2004) Production and release of neuroprotective tumor necrosis factor by P2X7 receptor-activated microglia. J Neurosci 24:1–7
Takenouchi T, Ogihara K, Sato M et al (2005) Inhibitory effects of U73122 and U73343 on Ca2+ influx and pore formation induced by the activation of P2X7 nucleotide receptors in mouse microglial cell line. Biochim Biophys Acta 1726:177–186
Takenouchi T, Iwamaru Y, Imamura M et al (2007a) Prion infection correlates with hypersensitivity of P2X7 nucleotide receptor in a mouse microglial cell line. FEBS Lett 581:3019–3026
Takenouchi T, Sato M, Kitani H (2007b) Lysophosphatidylcholine potentiates Ca2+ influx, pore formation and p44/42 MAP kinase phosphorylation mediated by P2X7 receptor activation in mouse microglial cells. J Neurochem 102:1518–1532
Takenouchi T, Iwamaru Y, Sugama S et al (2008) Lysophospholipids and ATP mutually suppress maturation and release of IL-1β in mouse microglial cells using a Rho-dependent pathway. J Immunol 180:7827–7839
Takenouchi T, Nakai M, Iwamaru Y et al (2009a) The activation of P2X7 receptor impairs lysosomal functions and stimulates the release of autophagolysosomes in microglial cells. J Immunol 182:2051–2062
Takenouchi T, Sugama S, Iwamaru Y et al (2009b) Modulation of the ATP-induced release and processing of IL-1β in microglial cells. Crit Rev Immunol 29:335–345
The Huntington’s Disease Collaboratine Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983
Varma H, Cheng R, Voisine C et al (2007) Inhibitors of metabolism rescue cell death in Huntington’s disease models. Proc Natl Acad Sci USA 104:14525–14530
Acknowledgments
This work was supported by a grant-in-aid from the Japanese Ministry of Education, Culture, Sports, Science, and Technology. This work was also supported by a research grant from the Takeda Science Foundation.
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Takenouchi, T., Sekiyama, K., Sekigawa, A. et al. P2X7 Receptor Signaling Pathway as a Therapeutic Target for Neurodegenerative Diseases. Arch. Immunol. Ther. Exp. 58, 91–96 (2010). https://doi.org/10.1007/s00005-010-0069-y
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DOI: https://doi.org/10.1007/s00005-010-0069-y