906
Views
48
CrossRef citations to date
0
Altmetric
Review Article

The potential role of proinflammatory and antiinflammatory cytokines in Alzheimer disease pathogenesis

&
Pages 881-895 | Received 21 Feb 2012, Accepted 18 Jun 2012, Published online: 13 Sep 2012

References

  • Passos, G.F., Figueiredo, C.P., Prediger, R.D., Silva, K.A., Siqueira, J.M., Duarte, F.S., Leal, P.C., et al. Involvement of phosphoinositide 3-kinase gamma in the neuro-inflammatory response and cognitive impairments induced by beta-amyloid 1-40 peptide in mice. Brain Behav Immun 2010, 24, 493–501.
  • Higuchi, M., Hatta, K., Honma, T., Hitomi, Y.H., Kambayashi, Y., Hibino, Y., Matsuzaki, I., et al. Association between altered systemic inflammatory interleukin-1beta and natural killer cell activity and subsequently agitation in patients with Alzheimer disease. Int J Geriatr Psychiatry 2010, 25, 604–611.
  • Vassar, R., Bennett, B.D., Babu-Khan, S., Kahn, S., Mendiaz, E.A., Denis, P., Teplow, D.B., et al. Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999, 286, 735–741.
  • Craddock, T.J., Tuszynski, J.A., Chopra, D., Casey, N., Goldstein, L.E., Hameroff, S.R., Tanzi, R.E. The zinc dyshomeostasis hypothesis of Alzheimer’s disease. PLoS ONE 2012, 7, e33552.
  • Sarajärvi, T., Helisalmi, S., Antikainen, L., Mäkinen, P., Koivisto, A.M., Herukka, S.K., Haapasalo, A., et al. An association study of 21 potential Alzheimer’s disease risk genes in a Finnish population. J Alzheimers Dis 2010, 21, 763–767.
  • Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., Small, G.W., Roses, A.D., et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993, 261, 921–923.
  • Strittmatter, W.J., Saunders, A.M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G.S., Roses, A.D. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 1993, 90, 1977–1981.
  • Mahley, R.W., Huang, Y., Weisgraber, K.H. Putting cholesterol in its place: apoE and reverse cholesterol transport. J Clin Invest 2006, 116, 1226–1229.
  • Morgan, K. The three new pathways leading to Alzheimer’s disease. Neuropathol Appl Neurobiol 2011, 37, 353–357.
  • Naj, A.C., Jun, G., Beecham, G.W., Wang, L.S., Vardarajan, B.N., Buros, J., Gallins, P.J., et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet 2011, 43, 436–441.
  • Hollingworth, P., Harold, D., Sims, R., Gerrish, A., Lambert, J.C., Carrasquillo, M.M., Abraham, R., et al.; Alzheimer’s Disease Neuroimaging Initiative; CHARGE consortium; EADI1 consortium. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet 2011, 43, 429–435.
  • Carrasquillo, M.M., Belbin, O., Hunter, T.A., Ma, L., Bisceglio, G.D., Zou, F., Crook, J.E., et al. Replication of CLU, CR1, and PICALM associations with alzheimer disease. Arch Neurol 2010, 67, 961–964.
  • Lee, J.H., Cheng, R., Barral, S., Reitz, C., Medrano, M., Lantigua, R., Jiménez-Velazquez, I.Z., et al. Identification of novel loci for Alzheimer disease and replication of CLU, PICALM, and BIN1 in Caribbean Hispanic individuals. Arch Neurol 2011, 68, 320–328.
  • Olgiati, P., Politis, A., Malitas, P., Albani, D., Dusi, S., Polito, L., De Mauro, S., et al. APOE epsilon-4 allele and cytokine production in Alzheimer’s disease. Int J Geriatr Psychiatry 2010, 25, 338–344.
  • Lio, D., Licastro, F., Scola, L., Chiappelli, M., Grimaldi, L.M., Crivello, A., Colonna-Romano, G., et al. Interleukin-10 promoter polymorphism in sporadic Alzheimer’s disease. Genes Immun 2003, 4, 234–238.
  • Laws, S.M., Perneczky, R., Wagenpfeil, S., Müller, U., Förstl, H., Martins, R.N., Kurz, A., Riemenschneider, M. TNF polymorphisms in Alzheimer disease and functional implications on CSF beta-amyloid levels. Hum Mutat 2005, 26, 29–35.
  • Vepsäläinen, S., Helisalmi, S., Mannermaa, A., Pirttilä, T., Soininen, H., Hiltunen, M. Combined risk effects of IDE and NEP gene variants on Alzheimer disease. J Neurol Neurosurg Psychiatr 2009, 80, 1268–1270.
  • Zou, F., Carrasquillo, M.M., Pankratz, V.S., Belbin, O., Morgan, K., Allen, M., Wilcox, S.L., et al. Gene expression levels as endophenotypes in genome-wide association studies of Alzheimer disease. Neurology 2010, 74, 480–486.
  • Farfara, D., Lifshitz, V., Frenkel, D. Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer’s disease. J Cell Mol Med 2008, 12, 762–780.
  • McGeer, E.G., McGeer, P.L. Neuroinflammation in Alzheimer’s disease and mild cognitive impairment: a field in its infancy. J Alzheimers Dis 2010, 19, 355–361.
  • Lee, K.S., Chung, J.H., Choi, T.K., Suh, S.Y., Oh, B.H., Hong, C.H. Peripheral cytokines and chemokines in Alzheimer’s disease. Dement Geriatr Cogn Disord 2009, 28, 281–287.
  • Agostinho, P., Cunha, R.A., Oliveira, C. Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer’s disease. Curr Pharm Des 2010, 16, 2766–2778.
  • Mrak, R.E. Neuropathology and the neuroinflammation idea. J Alzheimers Dis 2009, 18, 473–481.
  • Shaftel, S.S., Kyrkanides, S., Olschowka, J.A., Miller, J.N., Johnson, R.E., O’Banion, M.K. Sustained hippocampal IL-1 beta overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology. J Clin Invest 2007, 117, 1595–1604.
  • Yamamoto, M., Kiyota, T., Horiba, M., Buescher, J.L., Walsh, S.M., Gendelman, H.E., Ikezu, T. 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 2007, 170, 680–692.
  • Tesseur, I., Zou, K., Esposito, L., Bard, F., Berber, E., Can, J.V., Lin, A.H., et al. Deficiency in neuronal TGF-beta signaling promotes neurodegeneration and Alzheimer’s pathology. J Clin Invest 2006, 116, 3060–3069.
  • Villanueva, E.B., Little, J.P., Lambeau, G., Klegeris, A. Secreted phospholipase A(2) group IIA is a neurotoxin released by stimulated human glial cells. Mol Cell Neurosci 2012, 49, 430–438.
  • Rojo, L.E., Fernández, J.A., Maccioni, A.A., Jimenez, J.M., Maccioni, R.B. Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer’s disease. Arch Med Res 2008, 39, 1–16.
  • Pabon, M.M., Bachstetter, A.D., Hudson, C.E., Gemma, C., Bickford, P.C. CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson’s disease. J Neuroinflammation 2011, 8, 9.
  • Michelucci, A., Heurtaux, T., Grandbarbe, L., Morga, E., Heuschling, P. Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: Effects of oligomeric and fibrillar amyloid-beta. J Neuroimmunol 2009, 210, 3–12.
  • Block, M.L. NADPH oxidase as a therapeutic target in Alzheimer’s disease. BMC Neurosci 2008, 9 Suppl 2, S8.
  • Shimizu, E., Kawahara, K., Kajizono, M., Sawada, M., Nakayama, H. IL-4-induced selective clearance of oligomeric beta-amyloid peptide(1-42) by rat primary type 2 microglia. J Immunol 2008, 181, 6503–6513.
  • Kanzawa, T., Sawada, M., Kato, K., Yamamoto, K., Mori, H., Tanaka, R. Differentiated regulation of allo-antigen presentation by different types of murine microglial cell lines. J Neurosci Res 2000, 62, 383–388.
  • Mantovani, A., Sozzani, S., Locati, M., Allavena, P., Sica, A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 2002, 23, 549–555.
  • Mantovani, A. The chemokine system: redundancy for robust outputs. Immunol Today 1999, 20, 254–257.
  • Bulgarelli, I., Tamiazzo, L., Bresciani, E., Rapetti, D., Caporali, S., Lattuada, D., Locatelli, V., Torsello, A. Desacyl-ghrelin and synthetic GH-secretagogues modulate the production of inflammatory cytokines in mouse microglia cells stimulated by beta-amyloid fibrils. J Neurosci Res 2009, 87, 2718–2727.
  • Reed-Geaghan, E.G., Savage, J.C., Hise, A.G., Landreth, G.E. CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. J Neurosci 2009, 29, 11982–11992.
  • Chandler, D., Woldu, A., Rahmadi, A., Shanmugam, K., Steiner, N., Wright, E., Benavente-García, O., et al. Effects of plant-derived polyphenols on TNF-alpha and nitric oxide production induced by advanced glycation endproducts. Mol Nutr Food Res 2010, 54 Suppl 2, S141–S150.
  • Nah, S.S., Choi, I.Y., Yoo, B., Kim, Y.G., Moon, H.B., Lee, C.K. Advanced glycation end products increases matrix metalloproteinase-1, -3, and -13, and TNF-alpha in human osteoarthritic chondrocytes. FEBS Lett 2007, 581, 1928–1932.
  • Yan, S.D., Bierhaus, A., Nawroth, P.P., Stern, D.M. RAGE and Alzheimer’s disease: a progression factor for amyloid-beta-induced cellular perturbation? J Alzheimers Dis 2009, 16, 833–843.
  • Fang, F., Lue, L.F., Yan, S., Xu, H., Luddy, J.S., Chen, D., Walker, D.G., et al. RAGE-dependent signaling in microglia contributes to neuroinflammation, Abeta accumulation, and impaired learning/memory in a mouse model of Alzheimer’s disease. FASEB J 2010, 24, 1043–1055.
  • Arancio, O., Zhang, H.P., Chen, X., Lin, C., Trinchese, F., Puzzo, D., Liu, S., et al. RAGE potentiates Abeta-induced perturbation of neuronal function in transgenic mice. EMBO J 2004, 23, 4096–4105.
  • Li, C., Zhao, R., Gao, K., Wei, Z., Yin, M.Y., Lau, L.T., Chui, D., Hoi Yu, A.C. Astrocytes: implications for neuroinflammatory pathogenesis of Alzheimer’s disease. Curr Alzheimer Res 2011, 8, 67–80.
  • Heneka, M.T., O’Banion, M.K., Terwel, D., Kummer, M.P. Neuroinflammatory processes in Alzheimer’s disease. J Neural Transm 2010, 117, 919–947.
  • Politis, A., Olgiati, P., Malitas, P., Albani, D., Signorini, A., Polito, L., De Mauro, S., et al. Vitamin B12 levels in Alzheimer’s disease: association with clinical features and cytokine production. J Alzheimers Dis 2010, 19, 481–488.
  • Ojala, J., Alafuzoff, I., Herukka, S.K., van Groen, T., Tanila, H., Pirttilä, T. Expression of interleukin-18 is increased in the brains of Alzheimer’s disease patients. Neurobiol Aging 2009, 30, 198–209.
  • Pellicanò, M., Bulati, M., Buffa, S., Barbagallo, M., Di Prima, A., Misiano, G., Picone, P., et al. Systemic immune responses in Alzheimer’s disease: in vitro mononuclear cell activation and cytokine production. J Alzheimers Dis 2010, 21, 181–192.
  • Speciale, L., Calabrese, E., Saresella, M., Tinelli, C., Mariani, C., Sanvito, L., Longhi, R., Ferrante, P. Lymphocyte subset patterns and cytokine production in Alzheimer’s disease patients. Neurobiol Aging 2007, 28, 1163–1169.
  • Oprica, M., Hjorth, E., Spulber, S., Popescu, B.O., Ankarcrona, M., Winblad, B., Schultzberg, M. Studies on brain volume, Alzheimer-related proteins and cytokines in mice with chronic overexpression of IL-1 receptor antagonist. J Cell Mol Med 2007, 11, 810–825.
  • Serretti, A., Olgiati, P., Politis, A., Malitas, P., Albani, D., Dusi, S., Polito, L., et al. Lack of association between interleukin-1 alpha rs1800587 polymorphism and Alzheimer’s disease in two Independent European samples. J Alzheimers Dis 2009, 16, 181–187.
  • Klimkowicz-Mrowiec, A., Marona, M., Wolkow, P., Maruszak, A., Styczynska, M., Barcikowska, M., Zekanowski, C., et al. Interleukin-1 gene -511 CT polymorphism and the risk of Alzheimer’s disease in a Polish population. Dement Geriatr Cogn Disord 2009, 28, 461–464.
  • Schmitt, T.L., Steiner, E., Klinger, P., Sztankay, A., Grubeck-Loebenstein, B. The production of an amyloidogenic metabolite of the Alzheimer amyloid beta precursor protein (APP) in thyroid cells is stimulated by interleukin 1 beta, but inhibited by interferon gamma. J Clin Endocrinol Metab 1996, 81, 1666–1669.
  • Shaftel, S.S., Griffin, W.S., O’Banion, M.K. The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective. J Neuroinflammation 2008, 5, 7.
  • Wong, M.L., Bongiorno, P.B., Rettori, V., McCann, S.M., Licinio, J. Interleukin (IL) 1beta, IL-1 receptor antagonist, IL-10, and IL-13 gene expression in the central nervous system and anterior pituitary during systemic inflammation: pathophysiological implications. Proc Natl Acad Sci USA 1997, 94, 227–232.
  • Lemere, C.A. A beneficial role for IL-1 beta in Alzheimer disease? J Clin Invest 2007, 117, 1483–1485.
  • El Khoury, J., Luster, A.D. Mechanisms of microglia accumulation in Alzheimer’s disease: therapeutic implications. Trends Pharmacol Sci 2008, 29, 626–632.
  • Ting, K.K., Brew, B., Guillemin, G. The involvement of astrocytes and kynurenine pathway in Alzheimer’s disease. Neurotox Res 2007, 12, 247–262.
  • Guillemin, G.J., Smith, D.G., Smythe, G.A., Armati, P.J., Brew, B.J. Expression of the kynurenine pathway enzymes in human microglia and macrophages. Adv Exp Med Biol 2003, 527, 105–112.
  • Stone, T.W. Neuropharmacology of quinolinic and kynurenic acids. Pharmacol Rev 1993, 45, 309–379.
  • Ting, K.K., Brew, B.J., Guillemin, G.J. Effect of quinolinic acid on human astrocytes morphology and functions: implications in Alzheimer’s disease. J Neuroinflammation 2009, 6, 36.
  • Forlenza, O.V., Diniz, B.S., Talib, L.L., Mendonça, V.A., Ojopi, E.B., Gattaz, W.F., Teixeira, A.L. Increased serum IL-1beta level in Alzheimer’s disease and mild cognitive impairment. Dement Geriatr Cogn Disord 2009, 28, 507–512.
  • de Souza, D.F., Leite, M.C., Quincozes-Santos, A., Nardin, P., Tortorelli, L.S., Rigo, M.M., Gottfried, C., et al. S100B secretion is stimulated by IL-1beta in glial cultures and hippocampal slices of rats: Likely involvement of MAPK pathway. J Neuroimmunol 2009, 206, 52–57.
  • Seripa, D., Matera, M.G., Dal Forno, G., Gravina, C., Masullo, C., Daniele, A., Binetti, G., et al. Genotypes and haplotypes in the IL-1 gene cluster: analysis of two genetically and diagnostically distinct groups of Alzheimer patients. Neurobiol Aging 2005, 26, 455–464.
  • Hu, J.L., Li, G., Zhou, D.X., Zou, Y.X., Zhu, Z.S., Xu, R.X., Jiang, X.D., Zeng, Y.J. Genetic analysis of interleukin-1A C(-889)T polymorphism with Alzheimer disease. Cell Mol Neurobiol 2009, 29, 81–85.
  • Tachida, Y., Nakagawa, K., Saito, T., Saido, T.C., Honda, T., Saito, Y., Murayama, S., et al. Interleukin-1 beta up-regulates TACE to enhance alpha-cleavage of APP in neurons: resulting decrease in Abeta production. J Neurochem 2008, 104, 1387–1393.
  • Candiotti, K.A., Yang, Z., Morris, R., Yang, J., Crescimone, N.A., Sanchez, G.C., et al. Polymorphism in the interleukin-1 receptor antagonist gene is associated with serum interleukin-1 receptor antagonist concentrations and postoperative opioid consumption. Anesthesiology 2011, 114, 1162–1168.
  • Wang, K.C., Wang, S.J., Fan, L.W., Cai, Z., Rhodes, P.G., Tien, L.T. Interleukin-1 receptor antagonist ameliorates neonatal lipopolysaccharide-induced long-lasting hyperalgesia in the adult rats. Toxicology 2011, 279, 123–129.
  • Kitazawa, M., Cheng, D., Tsukamoto, M.R., Koike, M.A., Wes, P.D., Vasilevko, V., Cribbs, D.H., LaFerla, F.M. Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal ß-catenin pathway function in an Alzheimer’s disease model. J Immunol 2011, 187, 6539–6549.
  • Paradowski, B., Celczynska, D., Dobosz, T., Noga, L. Polymorphism 174 G/C of interleukin 6 gene in Alzheimer’s disease–preliminary report. Neurol Neurochir Pol 2008, 42, 312–315.
  • Butterworth, R.F. Pathophysiology of hepatic encephalopathy: The concept of synergism. Hepatol Res 2008, 38, S116–S121.
  • Chakrabarty, P., Jansen-West, K., Beccard, A., Ceballos-Diaz, C., Levites, Y., Verbeeck, C., Zubair, A.C., et al. Massive gliosis induced by interleukin-6 suppresses Abeta deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J 2010, 24, 548–559.
  • Baranowska-Bik, A., Bik, W., Wolinska-Witort, E., Martynska, L., Chmielowska, M., Barcikowska, M., Baranowska, B. Plasma beta amyloid and cytokine profile in women with Alzheimer’s disease. Neuro Endocrinol Lett 2008, 29, 75–79.
  • Galimberti, D., Venturelli, E., Fenoglio, C., Guidi, I., Villa, C., Bergamaschini, L., Cortini, F., et al. Intrathecal levels of IL-6, IL-11 and LIF in Alzheimer’s disease and frontotemporal lobar degeneration. J Neurol 2008, 255, 539–544.
  • Ciaramella, A., Bizzoni, F., Salani, F., Vanni, D., Spalletta, G., Sanarico, N., Vendetti, S., et al. Increased pro-inflammatory response by dendritic cells from patients with Alzheimer’s disease. J Alzheimers Dis 2010, 19, 559–572.
  • Klimkowicz-Mrowiec, A., Wolkow, P., Spisak, K., Maruszak, A., Styczynska, M., Barcikowska, M., Szczudlik, A., Slowik, A. Interleukin-6 gene (-174 C/G) and apolipoprotein E gene polymorphisms and the risk of Alzheimer disease in a Polish population. Neurol Neurochir Pol 2010, 44, 537–541.
  • He, M.X., Yang, W.L., Zhang, M.M., Lian, Y.J., Hua, H.Y., Zeng, J.S., Zhang, L.R. Association between interleukin-6 gene promoter -572C/G polymorphism and the risk of sporadic Alzheimer’s disease. Neurol Sci 2010, 31, 165–168.
  • Shibata, N., Ohnuma, T., Takahashi, T., Baba, H., Ishizuka, T., Ohtsuka, M., Ueki, A., Nagao, M., Arai, H. Effect of IL-6 polymorphism on risk of Alzheimer disease: genotype-phenotype association study in Japanese cases. Am J Med Genet 2002, 114, 436–439.
  • Crisby, M., Rahman, S.M., Sylvén, C., Winblad, B., Schultzberg, M. Effects of high cholesterol diet on gliosis in apolipoprotein E knockout mice. Implications for Alzheimer’s disease and stroke. Neurosci Lett 2004, 369, 87–92.
  • Famer, D., Wahlund, L.O., Crisby, M. Rosuvastatin reduces microglia in the brain of wild type and ApoE knockout mice on a high cholesterol diet; implications for prevention of stroke and AD. Biochem Biophys Res Commun 2010, 402, 367–372.
  • Famer, D., Crisby, M. Rosuvastatin reduces gliosis and the accelerated weight gain observed in WT and ApoE-/- mice exposed to a high cholesterol diet. Neurosci Lett 2007, 419, 68–73.
  • Yu, J.T., Tan, L., Song, J.H., Sun, Y.P., Chen, W., Miao, D., Tian, Y. Interleukin-18 promoter polymorphisms and risk of late onset Alzheimer’s disease. Brain Res 2009, 1253, 169–175.
  • Alboni, S., Montanari, C., Benatti, C., Blom, J.M., Simone, M.L., Brunello, N., Caggia, F., et al. Constitutive and LPS-regulated expression of interleukin-18 receptor beta variants in the mouse brain. Brain Behav Immun 2011, 25, 483–493.
  • Alboni, S., Cervia, D., Ross, B., Montanari, C., Gonzalez, A.S., Sanchez-Alavez, M., Marcondes, M.C., et al. Mapping of the full length and the truncated interleukin-18 receptor alpha in the mouse brain. J Neuroimmunol 2009, 214, 43–54.
  • Sugama, S., Cho, B.P., Baker, H., Joh, T.H., Lucero, J., Conti, B. Neurons of the superior nucleus of the medial habenula and ependymal cells express IL-18 in rat CNS. Brain Res 2002, 958, 1–9.
  • Wheeler, R.D., Culhane, A.C., Hall, M.D., Pickering-Brown, S., Rothwell, N.J., Luheshi, G.N. Detection of the interleukin 18 family in rat brain by RT-PCR. Brain Res Mol Brain Res 2000, 77, 290–293.
  • Felderhoff-Mueser, U., Schmidt, O.I., Oberholzer, A., Bührer, C., Stahel, P.F. IL-18: a key player in neuroinflammation and neurodegeneration? Trends Neurosci 2005, 28, 487–493.
  • Conti, B., Park, L.C., Calingasan, N.Y., Kim, Y., Kim, H., Bae, Y., Gibson, G.E., Joh, T.H. Cultures of astrocytes and microglia express interleukin 18. Brain Res Mol Brain Res 1999, 67, 46–52.
  • Bossù, P., Ciaramella, A., Salani, F., Bizzoni, F., Varsi, E., Di Iulio, F., Giubilei, F., et al. Interleukin-18 produced by peripheral blood cells is increased in Alzheimer’s disease and correlates with cognitive impairment. Brain Behav Immun 2008, 22, 487–492.
  • Segat, L., Milanese, M., Arosio, B., Vergani, C., Crovella, S. Lack of association between Interleukin-18 gene promoter polymorphisms and onset of Alzheimer’s disease. Neurobiol Aging 2010, 31, 162–164.
  • Engelborghs, S., De Brabander, M., De Crée, J., D’Hooge, R., Geerts, H., Verhaegen, H., De Deyn, P.P. Unchanged levels of interleukins, neopterin, interferon-gamma and tumor necrosis factor-alpha in cerebrospinal fluid of patients with dementia of the Alzheimer type. Neurochem Int 1999, 34, 523–530.
  • Kawanokuchi, J., Mizuno, T., Takeuchi, H., Kato, H., Wang, J., Mitsuma, N., Suzumura, A. Production of interferon-gamma by microglia. Mult Scler 2006, 12, 558–564.
  • Fitzner, D., Schnaars, M., van Rossum, D., Krishnamoorthy, G., Dibaj, P., Bakhti, M., Regen, T., et al. Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis. J Cell Sci 2011, 124, 447–458.
  • Baron, R., Nemirovsky, A., Harpaz, I., Cohen, H., Owens, T., Monsonego, A. IFN-gamma enhances neurogenesis in wild-type mice and in a mouse model of Alzheimer’s disease. FASEB J 2008, 22, 2843–2852.
  • Tobinick, E. Tumour necrosis factor modulation for treatment of Alzheimer’s disease: rationale and current evidence. CNS Drugs 2009, 23, 713–725.
  • Park, K.M., Bowers, W.J. Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction. Cell Signal 2010, 22, 977–983.
  • Tobinick, E. Perispinal etanercept for treatment of Alzheimer’s disease. Curr Alzheimer Res 2007, 4, 550–552.
  • Tobinick, E. Perispinal etanercept for neuroinflammatory disorders. Drug Discov Today 2009, 14, 168–177.
  • Pardridge, W.M. Biologic TNFa-inhibitors that cross the human blood-brain barrier. Bioeng Bugs 2010, 1, 231–234.
  • McCoy, M.K., Tansey, M.G. TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation 2008, 5, 45.
  • McAlpine, F.E., Lee, J.K., Harms, A.S., Ruhn, K.A., Blurton-Jones, M., Hong, J., Das, P., et al. Inhibition of soluble TNF signaling in a mouse model of Alzheimer’s disease prevents pre-plaque amyloid-associated neuropathology. Neurobiol Dis 2009, 34, 163–177.
  • Park, K.M., Yule, D.I., Bowers, W.J. Impaired TNF-alpha control of IP3R-mediated Ca2+ release in Alzheimer’s disease mouse neurons. Cell Signal 2010, 22, 519–526.
  • Kim, M.L., Zhang, B., Mills, I.P., Milla, M.E., Brunden, K.R., Lee, V.M. Effects of TNFalpha-converting enzyme inhibition on amyloid beta production and APP processing in vitro and in vivo. J Neurosci 2008, 28, 12052–12061.
  • Di Bona, D., Candore, G., Franceschi, C., Licastro, F., Colonna-Romano, G., Cammà, C., Lio, D., Caruso, C. Systematic review by meta-analyses on the possible role of TNF-alpha polymorphisms in association with Alzheimer’s disease. Brain Res Rev 2009, 61, 60–68.
  • Wang, B., Zhou, S., Yang, Z., Xie, Y.C., Wang, J., Zhang, P., Lv, Z., et al. Genetic analysis of tumor necrosis factor-alpha (TNF-alpha) G-308A and Saitohin Q7R polymorphisms with Alzheimer’s disease. J Neurol Sci 2008, 270, 148–151.
  • Yang, L., Lu, R., Jiang, L., Liu, Z., Peng, Y. Expression and genetic analysis of tumor necrosis factor-alpha (TNF-alpha) G-308A polymorphism in sporadic Alzheimer’s disease in a Southern China population. Brain Res 2009, 1247, 178–181.
  • McCusker, S.M., Curran, M.D., Dynan, K.B., McCullagh, C.D., Urquhart, D.D., Middleton, D., Patterson, C.C., et al. Association between polymorphism in regulatory region of gene encoding tumour necrosis factor alpha and risk of Alzheimer’s disease and vascular dementia: a case-control study. Lancet 2001, 357, 436–439.
  • Buchhave, P., Zetterberg, H., Blennow, K., Minthon, L., Janciauskiene, S., Hansson, O. Soluble TNF receptors are associated with Aß metabolism and conversion to dementia in subjects with mild cognitive impairment. Neurobiol Aging 2010, 31, 1877–1884.
  • Grell, M. Tumor necrosis factor (TNF) receptors in cellular signaling of soluble and membrane-expressed TNF. J Inflamm 1995, 47, 8–17.
  • Cheng, X., Yang, L., He, P., Li, R., Shen, Y. Differential activation of tumor necrosis factor receptors distinguishes between brains from Alzheimer’s disease and non-demented patients. J Alzheimers Dis 2010, 19, 621–630.
  • He, P., Zhong, Z., Lindholm, K., Berning, L., Lee, W., Lemere, C., Staufenbiel, M., et al. Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer’s mice. J Cell Biol 2007, 178, 829–841.
  • Dolga, A.M., Nijholt, I.M., Ostroveanu, A., Ten Bosch, Q., Luiten, P.G., Eisel, U.L. Lovastatin induces neuroprotection through tumor necrosis factor receptor 2 signaling pathways. J Alzheimers Dis 2008, 13, 111–122.
  • Marchetti, L., Klein, M., Schlett, K., Pfizenmaier, K., Eisel, U.L. Tumor necrosis factor (TNF)-mediated neuroprotection against glutamate-induced excitotoxicity is enhanced by N-methyl-D-aspartate receptor activation. Essential role of a TNF receptor 2-mediated phosphatidylinositol 3-kinase-dependent NF-kappa B pathway. J Biol Chem 2004, 279, 32869–32881.
  • Uberti, D., Cantarella, G., Facchetti, F., Cafici, A., Grasso, G., Bernardini, R., Memo, M. TRAIL is expressed in the brain cells of Alzheimer’s disease patients. Neuroreport 2004, 15, 579–581.
  • Hoffmann, O., Zipp, F., Weber, J.R. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in central nervous system inflammation. J Mol Med 2009, 87, 753–763.
  • Cui, M., Wang, L., Liang, X., Ma, X., Liu, Y., Yang, M., Liu, K., et al. Blocking TRAIL-DR5 signaling with soluble DR5 reduces delayed neuronal damage after transient global cerebral ischemia. Neurobiol Dis 2010, 39, 138–147.
  • Uberti, D., Ferrari-Toninelli, G., Bonini, S.A., Sarnico, I., Benarese, M., Pizzi, M., Benussi, L., et al. Blockade of the tumor necrosis factor-related apoptosis inducing ligand death receptor DR5 prevents beta-amyloid neurotoxicity. Neuropsychopharmacology 2007, 32, 872–880.
  • Lambracht-Washington, D., Qu, B.X., Fu, M., Anderson, L.D. Jr, Stüve, O., Eagar, T.N., Rosenberg, R.N. DNA immunization against amyloid beta 42 has high potential as safe therapy for Alzheimer’s disease as it diminishes antigen-specific Th1 and Th17 cell proliferation. Cell Mol Neurobiol 2011, 31, 867–874.
  • Mizuno, T., Doi, Y., Mizoguchi, H., Jin, S., Noda, M., Sonobe, Y., Takeuchi, H., Suzumura, A. Interleukin-34 selectively enhances the neuroprotective effects of microglia to attenuate oligomeric amyloid-ß neurotoxicity. Am J Pathol 2011, 179, 2016–2027.
  • da Rocha, M.D., Viegas, F.P., Campos, H.C., Nicastro, P.C., Fossaluzza, P.C., Fraga, C.A., Barreiro, E.J., Viegas, C. Jr. The role of natural products in the discovery of new drug candidates for the treatment of neurodegenerative disorders II: Alzheimer’s disease. CNS Neurol Disord Drug Targets 2011, 10, 251–270.
  • Montgomery, S.L., Mastrangelo, M.A., Habib, D., Narrow, W.C., Knowlden, S.A., Wright, T.W., Bowers, W.J. Ablation of TNF-RI/RII expression in Alzheimer’s disease mice leads to an unexpected enhancement of pathology: implications for chronic pan-TNF-a suppressive therapeutic strategies in the brain. Am J Pathol 2011, 179, 2053–2070.
  • Shi, J.Q., Shen, W., Chen, J., Wang, B.R., Zhong, L.L., Zhu, Y.W., Zhu, H.Q., et al. Anti-TNF-a reduces amyloid plaques and tau phosphorylation and induces CD11c-positive dendritic-like cell in the APP/PS1 transgenic mouse brains. Brain Res 2011, 1368, 239–247.
  • Minami, S.S., Sidahmed, E., Aid, S., Shimoji, M., Niikura, T., Mocchetti, I., Rebeck, G.W., et al. Therapeutic versus neuroinflammatory effects of passive immunization is dependent on Aß/amyloid burden in a transgenic mouse model of Alzheimer’s disease. J Neuroinflammation 2010, 7, 57.
  • Koronyo-Hamaoui, M., Ko, M.K., Koronyo, Y., Azoulay, D., Seksenyan, A., Kunis, G., Pham, M., et al. Attenuation of AD-like neuropathology by harnessing peripheral immune cells: local elevation of IL-10 and MMP-9. J Neurochem 2009, 111, 1409–1424.
  • Town, T., Laouar, Y., Pittenger, C., Mori, T., Szekely, C.A., Tan, J., Duman, R.S., Flavell, R.A. Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat Med 2008, 14, 681–687.
  • Lambert, K.E., Huang, H., Mythreye, K., Blobe, G.C. The type III transforming growth factor-ß receptor inhibits proliferation, migration, and adhesion in human myeloma cells. Mol Biol Cell 2011, 22, 1463–1472.
  • Basque, J., Martel, M., Leduc, R., Cantin, A.M. Lysosomotropic drugs inhibit maturation of transforming growth factor-beta. Can J Physiol Pharmacol 2008, 86, 606–612.
  • Mecha, M., Rabadán, M.A., Peña-Melián, A., Valencia, M., Mondéjar, T., Blanco, M.J. Expression of TGF-betas in the embryonic nervous system: analysis of interbalance between isoforms. Dev Dyn 2008, 237, 1709–1717.
  • Noguchi, A., Nawa, M., Aiso, S., Okamoto, K., Matsuoka, M. Transforming growth factor beta2 level is elevated in neurons of Alzheimer’s disease brains. Int J Neurosci 2010, 120, 168–175.
  • Peress, N.S., Perillo, E. Differential expression of TGF-beta 1, 2 and 3 isotypes in Alzheimer’s disease: a comparative immunohistochemical study with cerebral infarction, aged human and mouse control brains. J Neuropathol Exp Neurol 1995, 54, 802–811.
  • Tachi, N., Hashimoto, Y., Nawa, M., Matsuoka, M. TAG-1 is an inhibitor of TGFbeta2-induced neuronal death via amyloid beta precursor protein. Biochem Biophys Res Commun 2010, 394, 119–125.
  • Eslami, P., Johnson, M.F., Terzakaryan, E., Chew, C., Harris-White, M.E. TGF beta2-induced changes in LRP-1/T beta R-V and the impact on lysosomal A beta uptake and neurotoxicity. Brain Res 2008, 1241, 176–187.
  • Harris-White, M.E., Balverde, Z., Lim, G.P., Kim, P., Miller, S.A., Hammer, H., Galasko, D., Frautschy, S.A. Role of LRP in TGFbeta2-mediated neuronal uptake of Abeta and effects on memory. J Neurosci Res 2004, 77, 217–228.
  • Savvaki, M., Theodorakis, K., Zoupi, L., Stamatakis, A., Tivodar, S., Kyriacou, K., Stylianopoulou, F., Karagogeos, D. The expression of TAG-1 in glial cells is sufficient for the formation of the juxtaparanodal complex and the phenotypic rescue of tag-1 homozygous mutants in the CNS. J Neurosci 2010, 30, 13943–13954.
  • Savvaki, M., Panagiotaropoulos, T., Stamatakis, A., Sargiannidou, I., Karatzioula, P., Watanabe, K., Stylianopoulou, F., et al. Impairment of learning and memory in TAG-1 deficient mice associated with shorter CNS internodes and disrupted juxtaparanodes. Mol Cell Neurosci 2008, 39, 478–490.
  • Denaxa, M., Kyriakopoulou, K., Theodorakis, K., Trichas, G., Vidaki, M., Takeda, Y., Watanabe, K., Karagogeos, D. The adhesion molecule TAG-1 is required for proper migration of the superficial migratory stream in the medulla but not of cortical interneurons. Dev Biol 2005, 288, 87–99.
  • Soares, S., Traka, M., von Boxberg, Y., Bouquet, C., Karagogeos, D., Nothias, F. Neuronal and glial expression of the adhesion molecule TAG-1 is regulated after peripheral nerve lesion or central neurodegeneration of adult nervous system. Eur J Neurosci 2005, 21, 1169–1180.
  • Caraci, F., Spampinato, S., Sortino, M.A., Bosco, P., Battaglia, G., Bruno, V., Drago, F., et al. Dysfunction of TGF-ß1 signaling in Alzheimer’s disease: perspectives for neuroprotection. Cell Tissue Res 2012, 347, 291–301.
  • Tesseur, I., Zhang, H., Brecht, W., Corn, J., Gong, J.S., Yanagisawa, K., Michikawa, M., et al. Bioactive TGF-beta can associate with lipoproteins and is enriched in those containing apolipoprotein E3. J Neurochem 2009, 110, 1254–1262.
  • Ongali, B., Nicolakakis, N., Lecrux, C., Aboulkassim, T., Rosa-Neto, P., Papadopoulos, P., Tong, X.K., Hamel, E. Transgenic mice overexpressing APP and transforming growth factor-beta1 feature cognitive and vascular hallmarks of Alzheimer’s disease. Am J Pathol 2010, 177, 3071–3080.
  • Salins, P., He, Y., Olson, K., Glazner, G., Kashour, T., Amara, F. TGF-beta1 is increased in a transgenic mouse model of familial Alzheimer’s disease and causes neuronal apoptosis. Neurosci Lett 2008, 430, 81–86.
  • Papadopoulos, P., Ongali, B., Hamel, E. Selective in vivo antagonism of endothelin receptors in transforming growth factor-beta1 transgenic mice that mimic the vascular pathology of Alzheimer’s disease. Can J Physiol Pharmacol 2010, 88, 652–660.
  • Rodríguez-Rodríguez, E., Sánchez-Juan, P., Mateo, I., Llorca, J., Infante, J., García-Gorostiaga, I., Berciano, J., Combarros, O. Serum levels and genetic variation of TGF-beta1 are not associated with Alzheimer’s disease. Acta Neurol Scand 2007, 116, 409–412.
  • Luedecking, E.K., DeKosky, S.T., Mehdi, H., Ganguli, M., Kamboh, M.I. Analysis of genetic polymorphisms in the transforming growth factor-beta1 gene and the risk of Alzheimer’s disease. Hum Genet 2000, 106, 565–569.
  • Mocali, A., Cedrola, S., Della Malva, N., Bontempelli, M., Mitidieri, V.A., Bavazzano, A., Comolli, R., et al. Increased plasma levels of soluble CD40, together with the decrease of TGF beta 1, as possible differential markers of Alzheimer disease. Exp Gerontol 2004, 39, 1555–1561.
  • King, V.R., Phillips, J.B., Brown, R.A., Priestley, J.V. The effects of treatment with antibodies to transforming growth factor beta1 and beta2 following spinal cord damage in the adult rat. Neuroscience 2004, 126, 173–183.
  • Lue, L.F., Kuo, Y.M., Beach, T., Walker, D.G. Microglia activation and anti-inflammatory regulation in Alzheimer’s disease. Mol Neurobiol 2010, 41, 115–128.
  • Lyons, A., McQuillan, K., Deighan, B.F., O’Reilly, J.A., Downer, E.J., Murphy, A.C., Watson, M., et al. Decreased neuronal CD200 expression in IL-4-deficient mice results in increased neuroinflammation in response to lipopolysaccharide. Brain Behav Immun 2009, 23, 1020–1027.
  • Chao, C.C., Molitor, T.W., Hu, S. Neuroprotective role of IL-4 against activated microglia. J Immunol 1993, 151, 1473–1481.
  • Szczepanik, A.M., Funes, S., Petko, W., Ringheim, G.E. IL-4, IL-10 and IL-13 modulate A beta(1–42)-induced cytokine and chemokine production in primary murine microglia and a human monocyte cell line. J Neuroimmunol 2001, 113, 49–62.
  • Sholl-Franco, A., da Silva, A.G., Adão-Novaes, J. Interleukin-4 as a neuromodulatory cytokine: roles and signaling in the nervous system. Ann N Y Acad Sci 2009, 1153, 65–75.
  • Curbo, S., Gaudin, R., Carlsten, M., Malmberg, K.J., Troye-Blomberg, M., Ahlborg, N., Karlsson, A., et al. Regulation of interleukin-4 signaling by extracellular reduction of intramolecular disulfides. Biochem Biophys Res Commun 2009, 390, 1272–1277.
  • Kiyota, T., Okuyama, S., Swan, R.J., Jacobsen, M.T., Gendelman, H.E., Ikezu, T. CNS expression of anti-inflammatory cytokine interleukin-4 attenuates Alzheimer’s disease-like pathogenesis in APP+PS1 bigenic mice. FASEB J 2010, 24, 3093–3102.
  • Gambi, F., Reale, M., Iarlori, C., Salone, A., Toma, L., Paladini, C., De Luca, G., et al. Alzheimer patients treated with an AchE inhibitor show higher IL-4 and lower IL-1 beta levels and expression in peripheral blood mononuclear cells. J Clin Psychopharmacol 2004, 24, 314–321.
  • Colton, C.A., Mott, R.T., Sharpe, H., Xu, Q., Van Nostrand, W.E., Vitek, M.P. Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J Neuroinflammation 2006, 3, 27.
  • Wang, S., Wang, R., Chen, L., Bennett, D.A., Dickson, D.W., Wang, D.S. Expression and functional profiling of neprilysin, insulin-degrading enzyme, and endothelin-converting enzyme in prospectively studied elderly and Alzheimer’s brain. J Neurochem 2010, 115, 47–57.
  • Walker, D.G., Dalsing-Hernandez, J.E., Campbell, N.A., Lue, L.F. Decreased expression of CD200 and CD200 receptor in Alzheimer’s disease: a potential mechanism leading to chronic inflammation. Exp Neurol 2009, 215, 5–19.
  • Park, K.W., Baik, H.H., Jin, B.K. Interleukin-4-induced oxidative stress via microglial NADPH oxidase contributes to the death of hippocampal neurons in vivo. Curr Aging Sci 2008, 1, 192–201.
  • He, Y., Cui, J., Lee, J.C., Ding, S., Chalimoniuk, M., Simonyi, A., Sun, A.Y., et al. Prolonged exposure of cortical neurons to oligomeric amyloid-ß impairs NMDA receptor function via NADPH oxidase-mediated ROS production: protective effect of green tea (-)-epigallocatechin-3-gallate. ASN Neuro 2011, 3, e00050.
  • Ribizzi, G., Fiordoro, S., Barocci, S., Ferrari, E., Megna, M. Cytokine polymorphisms and Alzheimer disease: possible associations. Neurol Sci 2010, 31, 321–325.
  • Shibata, N., Ohnuma, T., Takahashi, T., Baba, H., Ishizuka, T., Ohtsuka, M., Ueki, A., et al. The effect of IL4 +33C/T polymorphism on risk of Japanese sporadic Alzheimer’s disease. Neurosci Lett 2002, 323, 161–163.
  • Fragoso, J.M., Vallejo, M., Alvarez-León, E., Delgadillo, H., Peña-Duque, M.A., Cardoso-Saldaña, G., Posadas-Romero, C., et al. Alleles and haplotypes of the interleukin 10 gene polymorphisms are associated with risk of developing acute coronary syndrome in Mexican patients. Cytokine 2011, 55, 29–33.
  • Jander, S., Pohl, J., D’Urso, D., Gillen, C., Stoll, G. Time course and cellular localization of interleukin-10 mRNA and protein expression in autoimmune inflammation of the rat central nervous system. Am J Pathol 1998, 152, 975–982.
  • Arosio, B., Mastronardi, L., Vergani, C., Annoni, G. Interleukin-10 promoter polymorphism in mild cognitive impairment and in its clinical evolution. Int J Alzheimers Dis 2010, 2010.
  • Szczepanik, A.M., Ringheim, G.E. IL-10 and glucocorticoids inhibit Abeta(1-42)- and lipopolysaccharide-induced pro-inflammatory cytokine and chemokine induction in the central nervous system. J Alzheimers Dis 2003, 5, 105–117.
  • Zocchia, C., Spiga, G., Rabin, S.J., Grekova, M., Richert, J., Chernyshev, O., Colton, C., Mocchetti, I. Biological activity of interleukin-10 in the central nervous system. Neurochem Int 1997, 30, 433–439.
  • Combarros, O., Sánchez-Juan, P., Riancho, J.A., Mateo, I., Rodríguez-Rodríguez, E., Infante, J., García-Gorostiaga, I., et al. Aromatase and interleukin-10 genetic variants interactively modulate Alzheimer’s disease risk. J Neural Transm 2008, 115, 863–867.
  • McNaull, B.B., Todd, S., McGuinness, B., Passmore, A.P. Inflammation and anti-inflammatory strategies for Alzheimer’s disease–a mini-review. Gerontology 2010, 56, 3–14.
  • Yu, D, Corbett, B, Yan, Y, Zhang, GX, Reinhart, P, Cho, SJ, Chin, J Early cerebrovascular inflammation in a transgenic mouse model of Alzheimer’s disease. Neurobiol Aging, 2012, (In Press).
  • Jaturapatporn, D., Isaac, M.G., McCleery, J., Tabet, N. Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer’s disease. Cochrane Database Syst Rev 2012, 2, CD006378.
  • van Exel, E., Eikelenboom, P., Comijs, H.C., Kurniawan, C., Frölich, M., Smit, J.H., Stek, M.L., et al. [The immune system and Alzheimer’s disease]. Tijdschr Psychiatr 2011, 53, 637–643.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.