- Email: [email protected]
Does IFNγ play a role in neurodegeneration?
Journal of Neuroimmunology 116 Ž2001. 1–4 www.elsevier.comrlocaterjneuroin
Point of View
Does IFNg play a role in neurodegeneration? Imrich Blasko a , Gerhard Ransmayr a , Robert Veerhuis b, Piet Eikelenboom b, Beatrix Grubeck-Loebenstein c,) a
b
Department of Neurology, UniÕersity Hospital of Innsbruck, Innsbruck, Austria Departments of Psychiatry and Pathology, Research Institute of Neurosciences, Vrije UniÕersiteit Amsterdam, Amsterdam, Netherlands c Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria Received 22 January 2001; received in revised form 14 February 2001; accepted 15 February 2001
Keywords: Mouse trisomy-16; Down’s syndrome; IFNg; Amyloid beta; Alzheimer’s disease
We have read with great interest the article by Hallam et al. on an interferon-gamma ŽIFNg .-related inflammatory reaction in the trisomy 16 ŽTs16. mouse brain, which leads to caspase-1-mediated neuronal apoptosis ŽHallam et al., 2000.. Using whole-brain homogenates, the authors report increased levels of IFNg and Fas receptor immunoreactivity and about altered itracellular calcium and pH homeostasis in Ts16 mouse neurons. From these data, it is concluded that an IFNg-mediated, self-perpetuating, inflammatory reaction might be responsible for the loss of neuron viability in Down’s syndrome ŽDS.. We would like to strengthen the point that IFNg is an important mediator in the development of neurodegeneration by demonstrating that IFNg may exert its detrimental influence via several different modes of action ŽFig. 1.. The finding of Hallam et al. of increased IFNg levels in Ts16 mouse brain homogenates is in accord with DS being associated with unexpectedly high levels of IFNg-inducible gene products including Fas, complement components and neuronal HLA I ŽSeidl et al., 1999; Stoltzner et al., 2000; Torre et al., 1995.. Both types of trisomy have a third copy of a chromosome, which shares a large segment of genes thought to be responsible for the DS phenotype ŽKola and Hertzog, 1997.. Human DS-children are born with a brain function close to normal ŽKish et al., 1989., but early on develop cognitive and learning difficulties. By the age of 40, patients with DS display neurodegeneration of the Alzheimer’s disease ŽAD. type ŽNeve et al., 2000..
)
Corresponding author. Tel.: q43-512-583919-14; fax: q43-512583919-8. E-mail address: [email protected] ŽB. Grubeck-Loebenstein..
One pathological feature common to both AD and DS is increased production of the Amyloid Precursor Protein ŽAPP. which eventually leads to the deposition of Amyloid beta ŽAb . ŽNeve et al., 2000.. Apart from the overproduction of APP, DS- and AD-patients share a dysregulation in the immune system. In DS as well as in AD, alterations in the production of cytokines have been found. In the DS thymus, overexpression of IFNg and TNFa has been demonstrated and been linked to abnormal thymic anatomy ŽMurphy et al., 1992.. In addition, AD- and DS-patients both have elevated serum concentrations of IL-1b ŽGriffin et al., 1989.. An increased body load of IFNg has been indirectly confirmed in DS-patients by increased urinary ratios of neopterinrbiopterin ŽCattell et al., 1989; Torre et al., 1995.. IFNg is a classic T cell cytokine, which influences more than 200 genes ŽBoehm et al., 1997.. Data from the last decade intriguingly suggest that under certain conditions, IFNg can be produced in the brain. Thus, IFNg immunoreactivity and IFNg-gene expression have been detected in human sensory neurons ŽNeumann et al., 1997; Olsson et al., 1994.. It has also been shown that human neuroglial cells and rat primary astrocytes triggered by TNFa can produce IFNg ŽNitta et al., 1994; Xiao and Link, 1998.. In addition, activated T lymphocytes and natural killer cells can cross the blood–brain barrier ŽBBB. in an antigen-nonspecific manner as part of normal immunologic surveillance ŽGriffin, 1997; Wekerle et al., 1987.. T cells remain within the central nervous system ŽCNS., when they are specific for intracerebral antigens, while T cells without such specificity leave the brain or undergo apoptosis ŽIrani and Griffin, 1996.. T cells passing through the brain can thus also deliver IFNg to neurons. This mechanism is well documented in experi-
0165-5728r01r$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 5 - 5 7 2 8 Ž 0 1 . 0 0 2 7 9 - X
2
I. Blasko et al.r Journal of Neuroimmunology 116 (2001) 1–4
Fig. 1. Schematic representation of the potential role of IFNg in neurodegeneration: in the brain IFNg may be produced by glial cells, neurons, T lymphocytes or NK cells. It stimulates glial cell activation and causes the production of pro-inflammatory cytokines and free radicals. In combination with TNFa or IL-1b, it triggers the production of the Alzheimer b-amyloid by neuronal cells and astrocytes. IFNg may mediate neuronal cell death indirectly via Abrradical-induced cytotoxicity or directly by inducing the expression of factors associated with apoptosis including Fas receptor induction and caspase activation.
mental autoimmune encephalomyelitis induced by active immunisation with an autoantigen, in which T cells cross the BBB and produce IFNg following ŽRenno et al., 1994., but may also be of relevance in neurodegenerative disorders. The production of IFNg and other pro-inflammatory cytokines is particularly high in old age ŽMaes et al., 1999; Saurwein-Teissl et al., 2000., which is still the major risk factor for AD. Therefore, a dysregulation in the production of cytokines in old age could contribute to neurodegeneration of the AD type. Assuming that there is indeed an increase in the production of IFNg in the CNS in Ts16 mice, in healthy seniors as well as patients with DS or AD, a consecutive increase in the production of Ab could be expected. Recent data demonstrate that IFNg plays a crucial role in the induction of Ab 40 and Ab 42 production ŽBlasko et al., 1999; Blasko et al., 2000.. Neuronal as well as extraneuronal cells, which fail to produce Ab constitutively, can be triggered to secrete large amounts of the compound following cytokine treatment. While IFNg alone is only capable of inducing a weak response, Ab secretion and its cellular accumulation are greatly enhanced when combinations of IFNg with TNFa or IL-1b are added. Furthermore, IFNg
does not only stimulate the production of Ab peptides, but can also inhibit the secretion of the neuroprotective APPsa ŽBlasko et al., 1999.. This has been demonstrated in human neuronal cells, as well as in primary astrocytes isolated post mortem from AD-patients and healthy aged persons. IFNg overproduction in old age may explain why Ab serum levels continually increase after a person enters the sixth decade ŽYounkin et al., 2000.. It therefore seems likely that the degeneration of neurons in Ts16 mice, in DS and in AD is at least partly due to IFNg-triggered, Ab-mediated cellular stress ŽYan et al., 2000; Yatin et al., 1998.. Obviously, the importance of amyloid as a source of neurodegeneration remains controversial ŽStahl et al., 1998; Stoll et al., 1993., but there is now strong evidence that overproduction of Ab does not only lead to AD-like pathology, but also induces cognitive impairment ŽJanus et al., 2000; Naslund et al., 2000.. A direct connection between Ab and neuronal cell death seems thus highly likely. In addition to inducing Ab production, IFNg may still have further detrimental effects in the brain. Thus, IFNg increases the production of TNFa and oxygen radicals by microglial cells after their stimulation with Ab ŽMeda et al., 1995. and affects the expression of factors associated
I. Blasko et al.r Journal of Neuroimmunology 116 (2001) 1–4
with apoptosis ŽBoehm et al., 1997. including Fas receptor induction ŽOssina et al., 1997. and caspase activation ŽTakahashi et al., 1999.. Having established that IFNg can indeed play an important role in the development of neurodegeneration, the question arises how excess IFNg production could be suppressed for therapeutic purposes. Peripherally administered antibodies against Ab enter the CNS and reduce the pathology in a mouse model of AD ŽBard et al., 2000.. Although, less than 0.1% of the administered antibodies entered the brain, this amount was sufficient to reduce amyloid plaque pathology. Similarly, anti-IFNg antibodies could cross the BBB and reduce local IFNg production. IFNg receptor antagonist or soluble IFNg receptors might be additional candidates for therapeutic use in neurodegenerative disorders such as DS and AD. Anti-IFNg antibodies have been shown to prevent apoptosis in Ts16 mouse cortical neurons in vitro ŽHallam and Maroun, 1998.. Future experimental work should strive to demonstrate how these effects are brought about and which therapeutic agents and strategies are most suitable for clinical trials. Acknowledgements The authors’ work referred to in this article was supported by The Austrian Science Funds, Grant P12440MED, by The Austrian Federal Ministry of Education, Science and Culture and the European Community Project No.: QLRT-1999-02004 ŽMANAD.. References Bard, F., Cannon, C., Barbour, R., Burke, R.L., Games, D., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K., Khan, K., Kholodenko, D., Lee, M., Lieberburg, I., Motter, R., Nguyen, M., Soriano, F., Vasquez, N., Weiss, K., Welch, B., Seubert, P., Schenk, D., Yednock, T., 2000. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med. 6, 916–919. Blasko, I., Marx, F., Steiner, E., Hartmann, T., Grubeck-Loebenstein, B., 1999. TNFalpha plus IFNgamma induce the production of Alzheimer beta-amyloid peptides and decrease the secretion of APPs. FASEB J. 13, 63–68. Blasko, I., Veerhuis, R., Stampfer-Kountchev, M., Saurwein-Teissl, M., Eikelenboom, P., Grubeck-Loebenstein, B., 2000. Costimulatory effects of interferon-gamma and interleukin-1beta or tumor necrosis factor alpha on the synthesis of Abeta1-40 and Abeta1-42 by human astrocytes. Neurobiol. Dis. 7, 682–689. Boehm, U., Klamp, T., Groot, M., Howard, J.C., 1997. Cellular responses to interferon-gamma. Annu. Rev. Immunol. 15, 749–795. Cattell, R.J., Hamon, C.G., Corbett, J.A., Lejeune, J., Blair, J.A., 1989. Neopterin: biopterin ratios in Down’s syndrome. J. Neurol. Neurosurg. Psychiatry 52, 1015–1016. Griffin, D.E., 1997. Cytokines in the brain during viral infection: clues to HIV-associated dementia. J. Clin. Invest. 100, 2948–2951. Griffin, W.S., Stanley, L.C., Ling, C., White, L., MacLeod, V., Perrot, L.J., White, C.L.d., Araoz, C., 1989. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc. Natl. Acad. Sci. U. S. A. 86, 7611–7615.
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Hallam, D.M., Maroun, L.E., 1998. Anti-gamma interferon can prevent the premature death of trisomy 16 mouse cortical neurons in culture. Neurosci. Lett. 252, 17–20. Hallam, D.M., Capps, N.L., Travelstead, A.L., Brewer, G.J., Maroun, L.E., 2000. Evidence for an interferon-related inflammatory reaction in the trisomy 16 mouse brain leading to caspase-1-mediated neuronal apoptosis. J. Neuroimmunol. 110, 66–75. Irani, D.N., Griffin, D.E., 1996. Regulation of lymphocyte homing into the brain during viral encephalitis at various stages of infection. J. Immunol. 156, 3850–3857. Janus, C., Pearson, J., McLaurin, J., Mathews, P.M., Jiang, Y., Schmidt, S.D., Chishti, M.A., Horne, P., Heslin, D., French, J., Mount, H.T., Nixon, R.A., Mercken, M., Bergeron, C., Fraser, P.E., St. George-Hyslop, P., Westaway, D., 2000. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature 408, 979–982. Kish, S., Karlinsky, H., Becker, L., Gilbert, J., Rebbetoy, M., Chang, L.J., DiStefano, L., Hornykiewicz, O., 1989. Down’s syndrome individuals begin life with normal levels of brain cholinergic markers. J. Neurochem. 52, 1183–1187. Kola, I., Hertzog, P.J., 1997. Animal models in the study of the biological function of genes on human chromosome 21 and their role in the pathophysiology of Down syndrome. Hum. Mol. Genet. 6, 1713–1727. Maes, M., DeVos, N., Wauters, A., Demedts, P., Maurits, V.W., Neels, H., Bosmans, E., Altamura, C., Lin, A., Song, C., Vandenbroucke, M., Scharpe, S., 1999. Inflammatory markers in younger vs. elderly normal volunteers and in patients with Alzheimer’s disease. J. Psychiatr. Res. 33, 397–405. Meda, L., Cassatella, M.A., Szendrei, G.I., Otvos Jr., L., Baron, P., Villalba, M., Ferrari, D., Rossi, F., 1995. Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 374, 647–650. Murphy, M., Friend, D.S., Pike-Nobile, L., Epstein, L.B., 1992. Tumor necrosis factor-alpha and IFN-gamma expression in human thymus. Localization and overexpression in Down syndrome Žtrisomy 21.. J. Immunol. 149, 2506–2512. Naslund, J., Haroutunian, V., Mohs, R., Davis, K.L., Davies, P., Greengard, P., Buxbaum, J.D., 2000. Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. J. Am. Med. Assoc. 283, 1571–1577. Neumann, H., Schmidt, H., Wilharm, E., Behrens, L., Wekerle, H., 1997. Interferon gamma gene expression in sensory neurons: evidence for autocrine gene regulation. J. Exp. Med. 186, 2023–2031. Neve, R.L., McPhie, D.L., Chen, Y., 2000. Alzheimer’s disease: a dysfunction of the amyloid precursor protein Ž1.. Brain Res. 886, 54–66. Nitta, T., Ebato, M., Sato, K., Okumura, K., 1994. Expression of tumour necrosis factor-alpha, -beta and interferon-gamma genes within human neuroglial tumour cells and brain specimens. Cytokine 6, 171– 180. Olsson, T., Kelic, S., Edlund, C., Bakhiet, M., Hojeberg, B., van der Meide, P.H., Ljungdahl, A., Kristensson, K., 1994. Neuronal interferon-gamma immunoreactive molecule: bioactivities and purification. Eur. J. Immunol. 24, 308–314. Ossina, N.K., Cannas, A., Powers, V.C., Fitzpatrick, P.A., Knight, J.D., Gilbert, J.R., Shekhtman, E.M., Tomei, L.D., Umansky, S.R., Kiefer, M.C., 1997. Interferon-gamma modulates a p53-independent apoptotic pathway and apoptosis-related gene expression. J. Biol. Chem. 272, 16351–16357. Renno, T., Lin, J.Y., Piccirillo, C., Antel, J., Owens, T., 1994. Cytokine production by cells in cerebrospinal fluid during experimental allergic encephalomyelitis in SJLrJ mice. J. Neuroimmunol. 49, 1–7. Saurwein-Teissl, M., Blasko, I., Zisterer, K., Neuman, B., Lang, B., Grubeck-Loebenstein, B., 2000. An imbalance between pro- and anti-inflammatory cytokines, a characteristic feature of old age. Cytokine 12, 1160–1161. Seidl, R., Fang-Kircher, S., Bidmon, B., Cairns, N., Lubec, G., 1999.
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Apoptosis-associated proteins p53 and APO-1rFas ŽCD95. in brains of adult patients with Down syndrome. Neurosci. Lett. 260, 9–12. Stahl, T., Goldammer, A., Luschekina, E., Beck, M., Schliebs, R., Bigl, V., 1998. Long-term basal forebrain cholinergic-rich grafts derived from trisomy 16 mice do not develop beta-amyloid pathology and neurodegeneration but demonstrate neuroinflammatory responses. Int. J. Dev. Neurosci. 16, 763–775. Stoll, J., Balbo, A., Ault, B., Rapoport, S.I., Fine, A., 1993. Long-term transplants of mouse trisomy 16 hippocampal neurons, a model for Down’s syndrome, do not develop Alzheimer’s disease neuropathology. Brain Res. 610, 295–304. Stoltzner, S.E., Grenfell, T.J., Mori, C., Wisniewski, K.E., Wisniewski, T.M., Selkoe, D.J., Lemere, C.A., 2000. Temporal accrual of complement proteins in amyloid plaques in Down’s syndrome with Alzheimer’s disease. Am. J. Pathol. 156, 489–499. Takahashi, H., Nakamura, S., Asano, K., Kinouchi, M., Ishida-Yamamoto, A., Iizuka, H., 1999. Fas antigen modulates ultraviolet B-induced apoptosis of SVHK cells: sequential activation of caspases 8, 3, and 1 in the apoptotic process. Exp. Cell. Res. 249, 291–298.
Torre, D., Broggini, M., Zeroli, C., Agrifoglio, L., Botta, V., Casalone, R., Ferrario, G., 1995. Serum levels of gamma interferon in patients with Down’s syndrome. Infection 23, 66–67. Wekerle, H., Sun, D., Oropeza-Wekerle, R.L., Meyermann, R., 1987. Immune reactivity in the nervous system: modulation of T-lymphocyte activation by glial cells. J. Exp. Biol. 132, 43–57. Xiao, B.G., Link, H., 1998. IFN-gamma production of adult rat astrocytes triggered by TNF-alpha. NeuroReport 9, 1487–1490. Yan, S.D., Roher, A., Chaney, M., Zlokovic, B., Schmidt, A.M., Stern, D., 2000. Cellular cofactors potentiating induction of stress and cytotoxicity by amyloid beta-peptide. Biochim. Biophys. Acta 1502, 145–157. Yatin, S.M., Aksenova, M., Aksenov, M., Markesbery, W.R., Aulick, T., Butterfield, D.A., 1998. Temporal relations among amyloid betapeptide-induced free-radical oxidative stress, neuronal toxicity, and neuronal defensive responses. J. Mol. Neurosci. 11, 183–197. Younkin, S.G., Taner, N.E., Xin, T., Baker, M., Younkin, L., Hutton, M., 2000. Role of elevated amyloid b protein in patients with typical late onset Alzheimer’s disease. Neurobiol. Aging 21, S136.
Point of View
Does IFNg play a role in neurodegeneration? Imrich Blasko a , Gerhard Ransmayr a , Robert Veerhuis b, Piet Eikelenboom b, Beatrix Grubeck-Loebenstein c,) a
b
Department of Neurology, UniÕersity Hospital of Innsbruck, Innsbruck, Austria Departments of Psychiatry and Pathology, Research Institute of Neurosciences, Vrije UniÕersiteit Amsterdam, Amsterdam, Netherlands c Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria Received 22 January 2001; received in revised form 14 February 2001; accepted 15 February 2001
Keywords: Mouse trisomy-16; Down’s syndrome; IFNg; Amyloid beta; Alzheimer’s disease
We have read with great interest the article by Hallam et al. on an interferon-gamma ŽIFNg .-related inflammatory reaction in the trisomy 16 ŽTs16. mouse brain, which leads to caspase-1-mediated neuronal apoptosis ŽHallam et al., 2000.. Using whole-brain homogenates, the authors report increased levels of IFNg and Fas receptor immunoreactivity and about altered itracellular calcium and pH homeostasis in Ts16 mouse neurons. From these data, it is concluded that an IFNg-mediated, self-perpetuating, inflammatory reaction might be responsible for the loss of neuron viability in Down’s syndrome ŽDS.. We would like to strengthen the point that IFNg is an important mediator in the development of neurodegeneration by demonstrating that IFNg may exert its detrimental influence via several different modes of action ŽFig. 1.. The finding of Hallam et al. of increased IFNg levels in Ts16 mouse brain homogenates is in accord with DS being associated with unexpectedly high levels of IFNg-inducible gene products including Fas, complement components and neuronal HLA I ŽSeidl et al., 1999; Stoltzner et al., 2000; Torre et al., 1995.. Both types of trisomy have a third copy of a chromosome, which shares a large segment of genes thought to be responsible for the DS phenotype ŽKola and Hertzog, 1997.. Human DS-children are born with a brain function close to normal ŽKish et al., 1989., but early on develop cognitive and learning difficulties. By the age of 40, patients with DS display neurodegeneration of the Alzheimer’s disease ŽAD. type ŽNeve et al., 2000..
)
Corresponding author. Tel.: q43-512-583919-14; fax: q43-512583919-8. E-mail address: [email protected] ŽB. Grubeck-Loebenstein..
One pathological feature common to both AD and DS is increased production of the Amyloid Precursor Protein ŽAPP. which eventually leads to the deposition of Amyloid beta ŽAb . ŽNeve et al., 2000.. Apart from the overproduction of APP, DS- and AD-patients share a dysregulation in the immune system. In DS as well as in AD, alterations in the production of cytokines have been found. In the DS thymus, overexpression of IFNg and TNFa has been demonstrated and been linked to abnormal thymic anatomy ŽMurphy et al., 1992.. In addition, AD- and DS-patients both have elevated serum concentrations of IL-1b ŽGriffin et al., 1989.. An increased body load of IFNg has been indirectly confirmed in DS-patients by increased urinary ratios of neopterinrbiopterin ŽCattell et al., 1989; Torre et al., 1995.. IFNg is a classic T cell cytokine, which influences more than 200 genes ŽBoehm et al., 1997.. Data from the last decade intriguingly suggest that under certain conditions, IFNg can be produced in the brain. Thus, IFNg immunoreactivity and IFNg-gene expression have been detected in human sensory neurons ŽNeumann et al., 1997; Olsson et al., 1994.. It has also been shown that human neuroglial cells and rat primary astrocytes triggered by TNFa can produce IFNg ŽNitta et al., 1994; Xiao and Link, 1998.. In addition, activated T lymphocytes and natural killer cells can cross the blood–brain barrier ŽBBB. in an antigen-nonspecific manner as part of normal immunologic surveillance ŽGriffin, 1997; Wekerle et al., 1987.. T cells remain within the central nervous system ŽCNS., when they are specific for intracerebral antigens, while T cells without such specificity leave the brain or undergo apoptosis ŽIrani and Griffin, 1996.. T cells passing through the brain can thus also deliver IFNg to neurons. This mechanism is well documented in experi-
0165-5728r01r$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 5 - 5 7 2 8 Ž 0 1 . 0 0 2 7 9 - X
2
I. Blasko et al.r Journal of Neuroimmunology 116 (2001) 1–4
Fig. 1. Schematic representation of the potential role of IFNg in neurodegeneration: in the brain IFNg may be produced by glial cells, neurons, T lymphocytes or NK cells. It stimulates glial cell activation and causes the production of pro-inflammatory cytokines and free radicals. In combination with TNFa or IL-1b, it triggers the production of the Alzheimer b-amyloid by neuronal cells and astrocytes. IFNg may mediate neuronal cell death indirectly via Abrradical-induced cytotoxicity or directly by inducing the expression of factors associated with apoptosis including Fas receptor induction and caspase activation.
mental autoimmune encephalomyelitis induced by active immunisation with an autoantigen, in which T cells cross the BBB and produce IFNg following ŽRenno et al., 1994., but may also be of relevance in neurodegenerative disorders. The production of IFNg and other pro-inflammatory cytokines is particularly high in old age ŽMaes et al., 1999; Saurwein-Teissl et al., 2000., which is still the major risk factor for AD. Therefore, a dysregulation in the production of cytokines in old age could contribute to neurodegeneration of the AD type. Assuming that there is indeed an increase in the production of IFNg in the CNS in Ts16 mice, in healthy seniors as well as patients with DS or AD, a consecutive increase in the production of Ab could be expected. Recent data demonstrate that IFNg plays a crucial role in the induction of Ab 40 and Ab 42 production ŽBlasko et al., 1999; Blasko et al., 2000.. Neuronal as well as extraneuronal cells, which fail to produce Ab constitutively, can be triggered to secrete large amounts of the compound following cytokine treatment. While IFNg alone is only capable of inducing a weak response, Ab secretion and its cellular accumulation are greatly enhanced when combinations of IFNg with TNFa or IL-1b are added. Furthermore, IFNg
does not only stimulate the production of Ab peptides, but can also inhibit the secretion of the neuroprotective APPsa ŽBlasko et al., 1999.. This has been demonstrated in human neuronal cells, as well as in primary astrocytes isolated post mortem from AD-patients and healthy aged persons. IFNg overproduction in old age may explain why Ab serum levels continually increase after a person enters the sixth decade ŽYounkin et al., 2000.. It therefore seems likely that the degeneration of neurons in Ts16 mice, in DS and in AD is at least partly due to IFNg-triggered, Ab-mediated cellular stress ŽYan et al., 2000; Yatin et al., 1998.. Obviously, the importance of amyloid as a source of neurodegeneration remains controversial ŽStahl et al., 1998; Stoll et al., 1993., but there is now strong evidence that overproduction of Ab does not only lead to AD-like pathology, but also induces cognitive impairment ŽJanus et al., 2000; Naslund et al., 2000.. A direct connection between Ab and neuronal cell death seems thus highly likely. In addition to inducing Ab production, IFNg may still have further detrimental effects in the brain. Thus, IFNg increases the production of TNFa and oxygen radicals by microglial cells after their stimulation with Ab ŽMeda et al., 1995. and affects the expression of factors associated
I. Blasko et al.r Journal of Neuroimmunology 116 (2001) 1–4
with apoptosis ŽBoehm et al., 1997. including Fas receptor induction ŽOssina et al., 1997. and caspase activation ŽTakahashi et al., 1999.. Having established that IFNg can indeed play an important role in the development of neurodegeneration, the question arises how excess IFNg production could be suppressed for therapeutic purposes. Peripherally administered antibodies against Ab enter the CNS and reduce the pathology in a mouse model of AD ŽBard et al., 2000.. Although, less than 0.1% of the administered antibodies entered the brain, this amount was sufficient to reduce amyloid plaque pathology. Similarly, anti-IFNg antibodies could cross the BBB and reduce local IFNg production. IFNg receptor antagonist or soluble IFNg receptors might be additional candidates for therapeutic use in neurodegenerative disorders such as DS and AD. Anti-IFNg antibodies have been shown to prevent apoptosis in Ts16 mouse cortical neurons in vitro ŽHallam and Maroun, 1998.. Future experimental work should strive to demonstrate how these effects are brought about and which therapeutic agents and strategies are most suitable for clinical trials. Acknowledgements The authors’ work referred to in this article was supported by The Austrian Science Funds, Grant P12440MED, by The Austrian Federal Ministry of Education, Science and Culture and the European Community Project No.: QLRT-1999-02004 ŽMANAD.. References Bard, F., Cannon, C., Barbour, R., Burke, R.L., Games, D., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K., Khan, K., Kholodenko, D., Lee, M., Lieberburg, I., Motter, R., Nguyen, M., Soriano, F., Vasquez, N., Weiss, K., Welch, B., Seubert, P., Schenk, D., Yednock, T., 2000. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med. 6, 916–919. Blasko, I., Marx, F., Steiner, E., Hartmann, T., Grubeck-Loebenstein, B., 1999. TNFalpha plus IFNgamma induce the production of Alzheimer beta-amyloid peptides and decrease the secretion of APPs. FASEB J. 13, 63–68. Blasko, I., Veerhuis, R., Stampfer-Kountchev, M., Saurwein-Teissl, M., Eikelenboom, P., Grubeck-Loebenstein, B., 2000. Costimulatory effects of interferon-gamma and interleukin-1beta or tumor necrosis factor alpha on the synthesis of Abeta1-40 and Abeta1-42 by human astrocytes. Neurobiol. Dis. 7, 682–689. Boehm, U., Klamp, T., Groot, M., Howard, J.C., 1997. Cellular responses to interferon-gamma. Annu. Rev. Immunol. 15, 749–795. Cattell, R.J., Hamon, C.G., Corbett, J.A., Lejeune, J., Blair, J.A., 1989. Neopterin: biopterin ratios in Down’s syndrome. J. Neurol. Neurosurg. Psychiatry 52, 1015–1016. Griffin, D.E., 1997. Cytokines in the brain during viral infection: clues to HIV-associated dementia. J. Clin. Invest. 100, 2948–2951. Griffin, W.S., Stanley, L.C., Ling, C., White, L., MacLeod, V., Perrot, L.J., White, C.L.d., Araoz, C., 1989. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc. Natl. Acad. Sci. U. S. A. 86, 7611–7615.
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