Expression of interleukin-18 is increased in the brains of Alzheimer’s disease patients
Abstract
The inflammatory cytokines can initiate nerve cell degeneration and enhance the plaque production typically found in Alzheimer's disease (AD). Interleukin-18 (IL-18) is an inflammatory cytokine, which can induce the expression of interferon-gamma. This interleukin shares similarities with the IL-1 family of proteins. Like IL-1 beta, IL-18 is cleaved by caspase-1 (ICE) to an active secreted form. We examined the expressions of IL-18, -1 beta and ICE in different brain regions from AD patients that were categorized with respect to the Braak stage, and age-matched with non-demented controls. The levels of total-RNA and protein of IL-18 and ICE were increased, especially in the frontal lobe of AD patients and this change was not modified by ApoE genotype. Immunohistochemistry of AD brain samples detected IL-18 in microglia, astrocytes, and surprisingly in neurons, and it is also co-localized not only with amyloid-beta plaques but also with tau. In CSF, elevated IL-18 level was detected only in men and it also correlated with CSF tau in MCI. IL-18 may thus be a potential biomarker for men. Plasma levels of IL-18 showed no correlation with the disease. In conclusion, amyloid-beta may induce the synthesis of IL-18, and IL-18 kinases involved in tau phosphorylation as a part of the amyloid-associated inflammatory reaction.
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Higher expression of IL-1β and IL-18 has been reported in microglia, astrocytes, and neurons surrounding Aβ plaques or in plasma of AD patients.
“Inflammasome and its products have been implicated in AD pathogenesis since a higher expression of IL-1β and IL-18 has been reported in the microglia, astrocytes, and neurons that surround Aβ plaques or in the plasma of AD patients (221–225).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [223]
Cites
Single-Step Method of RNA Isolation by Acid Guanidinium Thiocyanate–Phenol–Chloroform Extraction
Chomczynski, P., & Sacchi, N. (1987) · Analytical Biochemistry · doi:10.1006/abio.1987.9999 · Cited by 65,240 · see citing works
Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction
Chomczyński, P., & Sacchi, N. (1987) · Analytical Biochemistry · doi:10.1016/0003-2697(87)90021-2 · Cited by 47,092 · see citing works
McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., & Stadlan, E. M. (1984) · Neurology · doi:10.1212/wnl.34.7.939 · Cited by 27,915 · see citing works
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · see citing works
Mirra, S. S., Heyman, A., McKeel, D., Sumi, S. M., Crain, B. J., Brownlee, L. M., Vogel, F. S., Hughes, J. P., Belle, G. V., Berg, L., et al. (1991) · Neurology · doi:10.1212/wnl.41.4.479 · Cited by 4,961 · see citing works
Cloning of a new cytokine that induces IFN-γ production by T cells
Okamura, H., Tsutsui, H., Komatsu, T., Yutsudo, M., Hakura, A., Tanimoto, T., Torigoe, K., Okura, T., Nukada, Y., Hattori, K., et al. (1995) · Nature · doi:10.1038/378088a0 · Cited by 2,602 · see citing works
Diagnosis of Alzheimer's Disease
Khachaturian, Z. S. (1985) · Archives of Neurology · doi:10.1001/archneur.1985.04060100083029 · Cited by 2,499 · see citing works
Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease
Gómez‐Isla, T., Hollister, R., West, H., Mui, S., Growdon, J. H., Petersen, R. C., Parisi, J. E., & Hyman, B. T. (1997) · Annals of Neurology · doi:10.1002/ana.410410106 · Cited by 1,489 · see citing works
Borchelt, D. R., Ratovitski, T., van Lare, J., Lee, M. K., Gonzales, V., Jenkins, N. A., Copeland, N. G., Price, D. L., & Sisodia, S. S. (1997) · Neuron · doi:10.1016/s0896-6273(00)80974-5 · Cited by 1,023 · see citing works
A new murine model of accelerated senescence
Takeda, T., HOSOKAWA, M., TAKESHITA, S., Irino, M., Higuchi, K., Matsushita, T., Tomita, Y., Yasuhira, K., Hamamoto, H., & Shimizu, K. (1981) · Mechanisms of Ageing and Development · doi:10.1016/0047-6374(81)90084-1 · Cited by 871 · see citing works
Griffin, W., Sheng, J. G., Royston, M., Gentleman, S., McKenzie, J., Graham, D. I., Roberts, G., & Mrak, R. (1998) · Brain Pathology · doi:10.1111/j.1750-3639.1998.tb00136.x · Cited by 751 · see citing works
Gerdes, N., Sukhova, G. K., Libby, P., Reynolds, R. S., Young, J. L., & Schönbeck, U. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20011022 · Cited by 508 · see citing works
Herzig, M. C., Winkler, D. T., Burgermeister, P., Pfeifer, M., Kohler, E., Schmidt, S. D., Danner, S., Abramowski, D., Stürchler-Pierrat, C., Bürki, K., et al. (2004) · Nature Neuroscience · doi:10.1038/nn1302 · Cited by 391 · see citing works
Liao, Y.-F., Wang, B.-J., Cheng, H.-T., Kuo, L.-H., & Wolfe, M. S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m402034200 · Cited by 389 · see citing works
Vandenabeele, P., & Fiers, W. (1991) · Immunology Today · doi:10.1016/0167-5699(91)90032-o · Cited by 264 · see citing works
Blasko, I., Veerhuis, R., Stampfer-Kountchev, M., Saurwein-Teissl, M., Eikelenboom, P., & Grubeck-Loebenstein, B. (2000) · Neurobiology of Disease · doi:10.1006/nbdi.2000.0321 · Cited by 258 · see citing works
Sporadic cerebral amyloid angiopathy: pathology, clinical implications, and possible pathomechanisms
Attems, J. (2005) · Acta Neuropathologica · doi:10.1007/s00401-005-1074-9 · Cited by 238 · see citing works
Mehlhorn, G., Hollborn, M., & Schliebs, R. (2000) · International Journal of Developmental Neuroscience · doi:10.1016/s0736-5748(00)00012-5 · Cited by 199 · see citing works
Excitotoxic Neurodegeneration in Alzheimer Disease
Olney, J. W. (1997) · Archives of Neurology · doi:10.1001/archneur.1997.00550220042012 · Cited by 190 · see citing works
Cultures of astrocytes and microglia express interleukin 18
Conti, B., Park, L. C. H., Calingasan, N. Y., Kim, Y., Kim, H., Bae, Y. M., Gibson, G. E., & Joh, T. H. (1999) · Molecular Brain Research · doi:10.1016/s0169-328x(99)00034-0 · Cited by 187 · see citing works
Yatsiv, I., Morganti-Kossmann, M. C., Perez, D. R., Dinarello, C. A., Novick, D., Rubinstein, M., Otto, V. I., Rancan, M., Kossmann, T., Redaelli, C., et al. (2002) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-200208000-00008 · Cited by 183 · see citing works
Brain interleukin-1 beta in Alzheimer's disease and vascular dementia.
Cacabelos, R., Alvarez, X. A., Fernández‐Novoa, L., Franco, A., Mangues, R., Pellicer, À., & Nishimura, T. (1994) · PubMed · Cited by 182 · see citing works
Determination by PCR-RFLP of apo E genotype in a Japanese population.
Tsukamoto, K., Watanabe, T., Matsushima, T., Kinoshita, M., Kato, H., Hashimoto, Y., Kurokawa, K., & TERAMOTO, T. (1993) · PubMed · Cited by 170 · see citing works
Tha, K. K., Okuma, Y., Miyazaki, H., Murayama, T., Uehara, T., Hatakeyama, R., Hayashi, Y., & Nomura, Y. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02883-3 · Cited by 163 · see citing works
Multiple sclerosis: Cytokine receptors on oligodendrocytes predict innate regulation
Cannella, B., & Raine, C. S. (2003) · Annals of Neurology · doi:10.1002/ana.10764 · Cited by 147 · see citing works
Curran, B. P., & O'Connor, J. J. (2001) · Neuroscience · doi:10.1016/s0306-4522(01)00405-5 · Cited by 138 · see citing works
Chandrasekar, B., Mummidi, S., Claycomb, W. C., Mestril, R., & Nemer, M. J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m411787200 · Cited by 125 · see citing works
Joosten, L. A. B., Radstake, T. R. D. J., Lubberts, E., van den Bersselaar, L. A. M., van Riel, P. L. C. M., van Lent, P. L. E. M., Barrera, P., & van den Berg, W. B. (2003) · Arthritis & Rheumatism · doi:10.1002/art.10814 · Cited by 121 · see citing works
Thomassen, E., Bird, T. A., Renshaw, B. R., Kennedy, M. K., & Sims, J. E. (1998) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.1998.18.1077 · Cited by 119 · see citing works
Hippocampal Aβ42 Levels Correlate with Spatial Memory Deficit in APP and PS1 Double Transgenic Mice
Puoliväli, J. T., Wang, J., Heikkinen, T., Heikkilä, M., Tapiola, T., van Groen, T., & Tanila, H. (2002) · Neurobiology of Disease · doi:10.1006/nbdi.2002.0481 · Cited by 118 · see citing works
Self-citationCaspase Gene Expression in the Brain as a Function of the Clinical Progression of Alzheimer Disease
Pompl, P. N., Yemul, S., Xiang, Z., Ho, L., Haroutunian, V., Purohit, D. P., Mohs, R. C., & Pasinetti, G. M. (2003) · Archives of Neurology · doi:10.1001/archneur.60.3.369 · Cited by 117 · see citing works
Suo, Z., Tan, J., Placzek, A., Crawford, F., Fang, C., & Mullan, M. (1998) · Brain Research · doi:10.1016/s0006-8993(98)00780-x · Cited by 116 · see citing works
Chitotriosidase and inflammatory mediator levels in Alzheimer's disease and cerebrovascular dementia
Rosa, M. D., dell'Ombra, N., Zambito, A. M., Malaguarnera, M., Nicoletti, F., & Malaguarnera, L. (2006) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2006.04780.x · Cited by 103 · see citing works
Neurons of the superior nucleus of the medial habenula and ependymal cells express IL-18 in rat CNS
Sugama, S., Cho, B. P., Baker, H., Joh, T. H., Lucero, J., & Conti, B. (2002) · Brain Research · doi:10.1016/s0006-8993(02)03363-2 · Cited by 102 · see citing works
Daily administration of interleukin-18 causes myocardial dysfunction in healthy mice
Woldbæk, P. R., Sande, J. B., Strømme, T. A., Lunde, P., Djurovic, S., Lyberg, T., Christensen, G., & Tønnessen, T. (2005) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01179.2004 · Cited by 97 · see citing works
Functional studies of Alzheimer's disease tau protein
Lu, Q., & Jg, W. (1993) · Journal of Neuroscience · doi:10.1523/jneurosci.13-02-00508.1993 · Cited by 96 · see citing works
Karni, A. (2002) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(02)00018-8 · Cited by 95 · see citing works
Hampel, H. J., Teipel, S. J., Padberg, F., Haslinger, A., Riemenschneider, M., Schwarz, M., Kötter, H. U., Scheloske, M., Buch, K., Stübner, S., et al. (1999) · Brain Research · doi:10.1016/s0006-8993(99)01146-4 · Cited by 93 · see citing works
Interleukin-18: Perspectives on the Newest Interleukin
Gillespie, M. T., & Horwood, N. J. (1998) · Cytokine & Growth Factor Reviews · doi:10.1016/s1359-6101(98)00004-5 · Cited by 83 · see citing works
Kim, Y.-M., Im, J. Y., Han, S. H., Kang, H. S., & Choi, I. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.6.3198 · Cited by 77 · see citing works
IL-6-mediated events in Alzheimer's disease pathology
Bauer, J., Strauss, S., Volk, B., & Berger, T. (1991) · Immunology Today · doi:10.1016/0167-5699(91)90148-m · Cited by 62 · see citing works
Lindberg, C., Chromek, M., Ahrengart, L., Brauner, A., Schultzberg, M., & Garlind, A. (2005) · Neurochemistry International · doi:10.1016/j.neuint.2005.01.004 · Cited by 57 · see citing works
Mattson, M. P., & Rydel, R. E. (1996) · Nature · doi:10.1038/382674a0 · Cited by 57 · see citing works
Eftekhari, P., Roegel, J., Lezoualc’h, F., Fischmeister, R., Imbs, J., & Hoebeke, J. (2001) · European Journal of Immunology · doi:10.1002/1521-4141(200102)31:2 · Cited by 56 · see citing works
Increased lnterleukin-1β Converting Enzyme Expression and Activity in Alzheimer Disease
Zhu, S., Sheng, J. G., Jones, R. A., Brewer, M. M., Zhou, X. Q., Mrak, R. E., & Griffin, W. S. T. (1999) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199906000-00002 · Cited by 52 · see citing works
Identification of a truncated IL-18Rβ mRNA: a putative regulator of IL-18 expressed in rat brain
André, R., Wheeler, R. D., Collins, P. D., et al. (2003) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2003.09.005 · Cited by 38 · see citing works
Expression of ced-3 and ced-9 homologs in Alzheimer"s disease cerebral cortex
Desjardins, P., & Ledoux, S. (1998) · Neuroscience Letters · doi:10.1016/s0304-3940(98)00138-4 · Cited by 34 · see citing works
Takeda, T., Higuchi, K., & Hosokawa, M. (1997) · ILAR Journal · doi:10.1093/ilar.38.3.109 · Cited by 30 · see citing works
Human brain tissue microarrays as a platform to investigate diseases of the nervous system
MARTIKAINEN, P. M., Louhelainen, A., Kauppinen, T., et al. (2006) · Brain Research · doi:10.1016/j.brainres.2006.03.044 · Cited by 20 · see citing works
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Rutsch, A., Kantsjö, J. B., & Ronchi, F. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.604179 · Cited by 821 · see citing works
Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer’s disease
Cai, Z., Hussain, M. D., & Yan, L.-J. (2014) · International Journal of Neuroscience · doi:10.3109/00207454.2013.833510 · Cited by 583 · see citing works
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Brosseron, F., Krauthausen, M., Kummer, M., & Heneka, M. T. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-8657-1 · Cited by 447 · see citing works
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Dionisio-Santos, D. A., Olschowka, J. A., & O’Banion, M. K. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1453-0 · Cited by 184 · see citing works
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Pandey, A., Bani, S., Dutt, P., Kumar Satti, N., Avtar Suri, K., & Nabi Qazi, G. (2018) · Cytokine · doi:10.1016/j.cyto.2017.10.019 · Cited by 104 · see citing works
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Self-citation
- Authors
- Ojala, J., Alafuzoff, I., Herukka, S.-K., van Groen, T., Tanila, H., & Pirttilä, T.
- Affiliations
- University of Eastern Finland (FI)
- Corresponding author
- Ojala, Johanna
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2009-02
- Volume
- 30
- Issue
- 2
- Pages
- 198-209
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2075539642
- Cited by
- 235
- References
- 49
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 19 · 2023: 20 · 2022: 10 · 2021: 19 · 2020: 17 · 2019: 18 · 2018: 12 · 2017: 15 · 2016: 15 · 2015: 8 · 2014: 16 · 2013: 8 · 2012: 9
- FWCI
- 4.45
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- IL-18, Alzheimer's disease, caspase-1, IL-1β, amyloid plaques, tau protein, microglia, astrocytes, neurons, cerebrospinal fluid biomarkers, mild cognitive impairment, Braak stages, APOE genotype, neuroinflammation, tau phosphorylation
- MeSH terms
- Alzheimer Disease, Brain, Humans, Up-Regulation, Cytokines, Caspase 1, Interleukin-18
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