The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases
Abstract
Cultured brain cells are capable of generating many molecules associated with inflammatory and immune functions. They constitute the endogenous immune response system of brain. They include complement proteins and their regulators, inflammatory cytokines, acute phase reactants and many proteases and protease inhibitors. Most of the proteins are made by microglia and astrocytes, but even neurons are producers. Many appear in association with Alzheimer disease lesions, indicating a state of chronic inflammation in Alzheimer disease brain. Such a state can apparently exist without stimulation by peripheral inflammatory mediators or the peripheral immune system. A strong inflammatory response may be autotoxic to neurons, exacerbating the fundamental pathology in Alzheimer disease and perhaps other neurological disorders. Autotoxic processes may contribute to cellular death in chronic inflammatory diseases affecting other parts of the body, suggesting the general therapeutic value of anti-inflammatory agents. With respect to Alzheimer disease, multiple epidemiological studies indicate that patients taking anti-inflammatory drugs or suffering from conditions in which such drugs are routinely used, have a decreased risk of developing Alzheimer disease. In one very preliminary clinical trial, the anti-inflammatory drug indomethacin arrested progress of the disease. New agents directed against the inflammatory processes revealed in studies of Alzheimer disease lesions may have broad therapeutic applications.
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These genes encode key products having relevant functions within the immune system, which seems to influence several neurodegenerative and mental diseases.
“Despite not being modeled in the pathway enrichment analysis and the lack of reported evidence of their possible relationship with AD, these genes encode key products having relevant functions within the immune system, which seems to influence several neurodegenerative and mental diseases.57, 58”
From APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer’s disease (2016) · cites this paper as [57]
Microglial activation and consequent neuroinflammation are substantially involved in the progression of neurodegenerative diseases.
“This activation and consequent neuroinflammation are substantially involved in the progression of neurodegenerative diseases (McGeer and McGeer, 1995)”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as McGeer and McGeer, 1995
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BackgroundAlzheimer’s Disease: The Challenge of the Second Century
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BackgroundCytokines and major depression
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“Now that the in vivo and in vitro properties of microglia have been more appropriately investigated (McGeer and McGeer, 1995; McGeer et al., 2000), it is well-known that their Ageing Res Rev. Author manuscript; available in PMC 2013 September 25.”
BackgroundNonsteroidal Antiinflammatory Drugs and the Risk of Alzheimer's Disease
in 't Veld, B. A., Ruitenberg, A., Hofman, A., Launer, L. J., van Duijn, C. M., Stijnen, T., Breteler, M. M. B., & Stricker, B. H. C. (2001) · New England Journal of Medicine · doi:10.1056/nejmoa010178 · Cited by 1,196 · see citing works
Benavente-García, O., & Castillo, J. (2008) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf8006568 · Cited by 1,158 · see citing works
In-vivo measurement of activated microglia in dementia
Cagnin, A., Brooks, D. J., Kennedy, A. M., Gunn, R. N., Myers, R., Turkheimer, F. E., Jones, T., & Banati, R. B. (2001) · The Lancet · doi:10.1016/s0140-6736(01)05625-2 · Cited by 1,054 · see citing works
Yrjänheikki, J., Kauppinen, T. M., Keinänen, R., Goldsteins, G., Chan, P. H., & Koıstınaho, J. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.23.13496 · Cited by 1,040 · see citing works
Alzheimer's amyloid fibrils: structure and assembly.
Serpell, L. (2000) · Biochimica et Biophysica Acta · doi:10.1016/s0925-4439(00)00029-6 · Cited by 922 · see citing works
Alzheimer's Disease--Genotypes, Phenotype, and Treatments
Selkoe, D. J. (1997) · Science · doi:10.1126/science.275.5300.630 · Cited by 871 · see citing works
A Review: Inflammatory Process in Alzheimer's Disease, Role of Cytokines
Rubio-Perez, J. M., & Morillas-Ruiz, J. M. (2012) · The Scientific World JOURNAL · doi:10.1100/2012/756357 · Cited by 841 · see citing works
“Conflict of Interests Authors declare no competing financial interests.”
BackgroundAnti-inflammatory drugs and their mechanism of action
Vane, J. R., & Botting, R. M. (1998) · Inflammation Research · doi:10.1007/s000110050284 · Cited by 801 · see citing works
Oxidative Alterations in Alzheimer's Disease
Markesbery, W. R., & Carney, J. M. (1999) · Brain Pathology · doi:10.1111/j.1750-3639.1999.tb00215.x · Cited by 789 · see citing works
Neuroprotection by Aspirin and Sodium Salicylate Through Blockade of NF-κB Activation
Grilli, M., Pizzi, M., Memo, M., & Spano, P. (1996) · Science · doi:10.1126/science.274.5291.1383 · Cited by 751 · see citing works
SIRT1 Protects against Microglia-dependent Amyloid-β Toxicity through Inhibiting NF-κB Signaling
Chen, J., Zhou, Y., Mueller-Steiner, S., Chen, L.-F., Kwon, H., Yi, S., Mucke, L., & Gan, L. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m509329200 · Cited by 740 · see citing works
The role of inflammation in Alzheimer’s disease
Tuppo, E. E., & Arias, H. R. (2005) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2004.07.009 · Cited by 734 · see citing works
Role of Microglia in Central Nervous System Infections
Rock, R. B., Gekker, G., Hu, S., Sheng, W. S., Cheeran, M., Lokensgard, J. R., & Peterson, P. K. (2004) · Clinical Microbiology Reviews · doi:10.1128/cmr.17.4.942-964.2004 · Cited by 723 · see citing works
Combs, C. K., Karlo, J. C., Kao, S.-C., & Landreth, G. E. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-04-01179.2001 · Cited by 721 · see citing works
“Indeed, abundant reactive microglia and astrocytes surround the b-amyloid plaques in the AD brain (Itagaki et al., 1989; Miyazono et al., 1991; McGeer and Rogers, 1992; McGeer and McGeer, 1995; Cotman et al., 1996).”
BackgroundInflammatory markers and cognition in well-functioning African-American and white elders
Yaffe, K., Lindquist, K., Penninx, B. W., Simonsick, E. M., Pahor, M., Kritchevsky, S., Launer, L., Kuller, L., Rubin, S., & Harris, T. (2003) · Neurology · doi:10.1212/01.wnl.0000073620.42047.d7 · Cited by 706 · see citing works
Nerve growth factor: from neurotrophin to neurokine
Levi‐Montalcini, R., Skaper, S. D., Toso, R. D., Petrelli, L., & Leon, A. (1996) · Trends in Neurosciences · doi:10.1016/s0166-2236(96)10058-8 · Cited by 684 · see citing works
Vascular risk factors for Alzheimer’s disease:
Breteler, M. M. B. (2000) · Neurobiology of Aging · doi:10.1016/s0197-4580(99)00110-4 · Cited by 664 · see citing works
Microglia in health and disease
Kim, S. U., & de Vellis, J. (2005) · Journal of Neuroscience Research · doi:10.1002/jnr.20562 · Cited by 663 · see citing works
Epidemiology of parkinson’s disease
Tanner, C. M., & Goldman, S. M. (1996) · Neurologic Clinics · doi:10.1016/s0733-8619(05)70259-0 · Cited by 640 · see citing works
Nonsteroidal Anti-inflammatory Drugs and the Risk of Parkinson Disease
Chen, H., Zhang, S. M., Hernán, M. Á., Schwarzschild, M. A., Willett, W. C., Colditz, G. A., Speizer, F. E., & Ascherio, A. (2003) · Archives of Neurology · doi:10.1001/archneur.60.8.1059 · Cited by 630 · see citing works
“Moreover, our results are also consistent with the previous epidemiological support of a protective effect of NSAIDs on the risk of Alzheimer disease,(8,9) for which similar biological hypotheses have been proposed.(6,7) A protective role of NSAIDs in the central nervous system seems therefore likely and should be add…”
DNA Replication Precedes Neuronal Cell Death in Alzheimer's Disease
Yang, Y., Geldmacher, D., & Herrup, K. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-08-02661.2001 · Cited by 607 · see citing works
“These latter data are particularly intriguing given the epidemiological findings of a protective effect of high doses of nonsteroidal anti-inflammatory drugs (P. McGeer and McGeer, 1995; E. G. McGeer and McGeer, 1997).”
ResultWhat is the role of protein aggregation in neurodegeneration?
Ross, C. A., & Poirier, M. A. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1742 · Cited by 604 · see citing works
“These aggregates can be targeted and partially engulfed by activated microglia, inducing an inflammatory response, and probably exacerbating, rather than ameliorating, amyloid-associated neurodegeneration in AD brai”
BackgroundIto, D., Tanaka, K., Suzuki, S., Dembo, T., & Fukuuchi, Y. (2001) · Stroke · doi:10.1161/01.str.32.5.1208 · Cited by 594 · see citing works
Amyloid cascade hypothesis: Pathogenesis and therapeutic strategies in Alzheimer's disease
Barage, S. H., & Sonawane, K. D. (2015) · Neuropeptides · doi:10.1016/j.npep.2015.06.008 · Cited by 579 · see citing works
“2) (Eikelenboom et al., 1994; McGeer and McGeer, 1995; Rogers et al., 1996).”
Inflammatory processes in Alzheimer's disease
Heneka, M. T., & O'Banion, M. K. (2007) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2006.11.017 · Cited by 782 · see citing works
“In turn, fibrillar Aβ has been reported to increase neurotoxic secretory products, proinflammatory cytokines and reactive oxygen species (Eikelenboom et al., 1994; McGeer and McGeer, 1995; Eikelenboom and van Gool, 2004).”
The impact of microglial activation on blood-brain barrier in brain diseases
da Fonseca, A. C. C., Matias, D., Garcia, C., Amaral, R., Geraldo, L. H., Freitas, C., & Lima, F. R. S. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00362 · Cited by 572 · see citing works
“Intravenous immunoglobulin increases the circulating levels of IL-1R antagonist (IL-1Ra), blocking IL-1β signaling (Crow et al., 2007; Mikati et al., 2010; Li et al., 2012).”
BackgroundThe peripheral benzodiazepine binding site in the brain in multiple sclerosis
Banati, R. B., Newcombe, J., Gunn, R. N., Cagnin, A., Turkheimer, F., Heppner, F., Price, G., Wegner, F., Giovannoni, G., Miller, D. H., et al. (2000) · Brain · doi:10.1093/brain/123.11.2321 · Cited by 661 · see citing works
“…are activated not only in inflammatory diseases, such as multiple sclerosis, but also in chronic neurodegenerative diseases, such as Alzheimer’s dementia, for which the potentially beneficial effects of antiinflammatory drug treatment are already under investigation (McGeer and McGeer, 1995).”
BackgroundCasserly, I., & Topol, E. J. (2004) · The Lancet · doi:10.1016/s0140-6736(04)15900-x · Cited by 560 · see citing works
Microglia as effector cells in brain damage and repair: focus on prostanoids and nitric oxide
Minghetti, L. (1998) · Progress in Neurobiology · doi:10.1016/s0301-0082(97)00052-x · Cited by 562 · see citing works
Combs, C. K., Johnson, D. E., Karlo, J. C., Cannady, S. B., & Landreth, G. E. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-02-00558.2000 · Cited by 483 · see citing works
“Increased expression of the b2-integrin CD11b/CD18 (MAC-1) by plaque-associated microglia in the AD brain (McGeer and McGeer, 1995) as well as its transgenic mouse models (Sturchler-Pierrat et al., 1997; Frautschy et al., 1998) has been reported.”
BackgroundInfluentialKamei, Y., Inagaki, N., Nishizawa, M., Tsutsumi, O., Taketani, Y., & Inagaki, M. (1998) · Glia · doi:10.1002/(sici)1098-1136(199807)23:3 · Cited by 114 · see citing works
Zinc Metabolism in the Brain: Relevance to Human Neurodegenerative Disorders
Cuajungco, M. P., & Lees, G. J. (1997) · Neurobiology of Disease · doi:10.1006/nbdi.1997.0163 · Cited by 540 · see citing works
Lee, W., Loo, C., Bebawy, M., Luk, F., Mason, R. S., & Rohanizadeh, R. (2013) · Current Neuropharmacology · doi:10.2174/1570159x11311040002 · Cited by 539 · see citing works
“Similar to the response evoked by microglia, astrocytes activated by A produced various pro-inflammatory compounds such as IL-1, IL-6, IL-18, TNF- , prostaglandins and ROS [241, 242].”
ResultLindqvist, D., Janelidze, S., Hagell, P., Erhardt, S., Samuelsson, M., Minthon, L., Hansson, O., Björkqvist, M., Träskman-Bendz, L., & Brundin, L. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.01.030 · Cited by 524 · see citing works
Inflammation and the Degenerative Diseases of Aging
McGeer, P. L., & McGeer, E. G. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1332.007 · Cited by 519 · see citing works
Self-citationColangelo, V., Schurr, J., Ball, M. J., Pelaez, R. P., Bazan, N. G., & Lukiw, W. J. (2002) · Journal of Neuroscience Research · doi:10.1002/jnr.10351 · Cited by 517 · see citing works
Essential fatty acids and the brain: possible health implications
Youdim, K. A., Martin, A., & Joseph, J. A. (2000) · International Journal of Developmental Neuroscience · doi:10.1016/s0736-5748(00)00013-7 · Cited by 517 · see citing works
Saurwein-Teissl, M., Lung, T. L., Marx, F., Gschösser, C., Asch, E., Blasko, I., Parson, W., Böck, G., Schönitzer, D., Trannoy, E., et al. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.11.5893 · Cited by 499 · see citing works
“Proinflammatory cytokines are now believed to exacerbate the functional pathology and disease course of agerelated disorders, such as Alzheimer’s disease (22, 23) and atherosclerosis (24).”
BackgroundNeurological mechanisms of green tea polyphenols in Alzheimer's and Parkinson's diseases
Weinreb, O., Mandel, S. A., Amit, T., & Youdim, M. B. H. (2004) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2004.05.002 · Cited by 506 · see citing works
“[75] McGeer PL, McGeer EG.”
Microglia during development and aging
Harry, G. J. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.04.013 · Cited by 524 · see citing works
“N IH -PA Author M anuscript N IH -PA Author M anuscript B cell markers such as various cluster of differentiation (CD) proteins (Perry et al., 1985; McGeer and McGeer, 1995; Williams et al., 1994).”
BackgroundInterleukin-6 (IL-6)—A molecule with both beneficial and destructive potentials
Gadient, R. A., & Otten, U. (1997) · Progress in Neurobiology · doi:10.1016/s0301-0082(97)00021-x · Cited by 481 · see citing works
Krabbe, G., Halle, A., Matyash, V., Rinnenthal, J. L., Eom, G. D., Bernhardt, U., Miller, K. R., Prokop, S., Kettenmann, H., & Heppner, F. L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0060921 · Cited by 478 · see citing works
“A number of in vitro studies have not only shown that administration of Ab stimulates the production of inflammatory cytokines and activation markers in microglial cells [8] but also triggers its uptake by receptor-mediated phagocytosis [16].”
BackgroundInflammation, autotoxicity and Alzheimer disease
McGeer, P. L. (2001) · Neurobiology of Aging · doi:10.1016/s0197-4580(01)00289-5 · Cited by 474 · see citing works
Self-citationInflammatory processes in amyotrophic lateral sclerosis
McGeer, P. L., & McGeer, E. G. (2002) · Muscle & Nerve · doi:10.1002/mus.10191 · Cited by 470 · see citing works
“ease, in which many accompanying inflammatory changes have been shown to occur.(80,88) Activated microglia, in particular, are a source of neurotoxic”
BackgroundSelf-citationInflammatory processes in Alzheimer's disease
McGeer, E. G., & McGeer, P. L. (2003) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/s0278-5846(03)00124-6 · Cited by 473 · see citing works
Self-citationAlzheimer's disease and oxidative stress: implications for novel therapeutic approaches
Behl, C. (1999) · Progress in Neurobiology · doi:10.1016/s0301-0082(98)00055-0 · Cited by 444 · see citing works
Inflammation and Alzheimer's disease pathogenesis
Rogers, J., Webster, S. D., Lue, L., Brachova, L., CIVIN, W. H., Emmerling, M. R., Shivers, B. D., Walker, D. G., & McGeer, P. L. (1996) · Neurobiology of Aging · doi:10.1016/0197-4580(96)00115-7 · Cited by 441 · see citing works
Self-citationThe role of astrocytes in amyloid production and Alzheimer's disease
Frost, G. R., & Li, Y. (2017) · Open Biology · doi:10.1098/rsob.170228 · Cited by 435 · see citing works
Neuroinflammatory processes in Alzheimer’s disease
Heneka, M. T., O’Banion, M. K., Terwel, D., & Kummer, M. P. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-010-0438-z · Cited by 433 · see citing works
“ucts, proinflammatory cytokines and reactive oxygen species (Eikelenboom and van Gool 2004; Eikelenboom et al. 1994; McGeer and McGeer 1995).”
BackgroundNeurodegenerative disorders: the role of peroxynitrite
Torreilles, F., Salman-Tabcheh, S., Guérin, M.-C., & Torreilles, J. (1999) · Brain Research Reviews · doi:10.1016/s0165-0173(99)00014-4 · Cited by 430 · see citing works
Visualising microglial activation in vivo
Banati, R. B. (2002) · Glia · doi:10.1002/glia.10144 · Cited by 428 · see citing works
“Some epidemiological studies have found a protective effect of antiinflammatory medication against the risk of developing late-onset Alzheimer-type dementia (McGeer and McGeer, 1995; in t’ Veld et al., 2001) that lends support to this view.”
BackgroundBerchtold, N. C., & Cotman, C. W. (1998) · Neurobiology of Aging · doi:10.1016/s0197-4580(98)00052-9 · Cited by 430 · see citing works
Santos, C. Y., Snyder, P. J., Wu, W., Zhang, M., Echeverria, A., & Alber, J. (2017) · Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring · doi:10.1016/j.dadm.2017.01.005 · Cited by 431 · see citing works
Inflammatory process in Alzheimer's Disease
Meraz-Ríos, M. A., Toral-Rios, D., Franco-Bocanegra, D., Villeda-Hernández, J., & Campos-Peña, V. (2013) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2013.00059 · Cited by 427 · see citing works
“…were designed based on the idea that the immune response in AD has an adverse effect (Blasko et al., 2004) or may be a causal factor (McGeer and McGeer, 1995), there are other approaches which suggest that the immune response may be beneficial because it attempts to counteract the deleterious…”
BackgroundStadelmann, C., Kerschensteiner, M., Misgeld, T., Brück, W., Hohlfeld, R., & Lassmann, H. (2002) · Brain · doi:10.1093/brain/awf015 · Cited by 425 · see citing works
“…into sites of neural injury seem to protect brainstem neurones after experimental trauma (Serpe et al., 1999) and could potentially do so in neurodegenerative diseases (Batchelor et al., 1999), which show substantial immune activation in foci of pathological change (McGeer and McGeer, 1995).”
BackgroundEssential Fatty Acids and the Brain
Haag, M. (2003) · The Canadian Journal of Psychiatry · doi:10.1177/070674370304800308 · Cited by 421 · see citing works
“The normal aging process is characterized by decreased delta-6desaturase activity (91,92), increased inflammatory response (93), and oxidative damage to the cell membrane (94).”
BackgroundOccurrence of T cells in the brain of Alzheimer's disease and other neurological diseases
Togo, T., Akiyama, H., Iseki, E., Kondo, H., Ikeda, K., Kato, M., Oda, T., Tsuchiya, K., & Kosaka, K. (2002) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(01)00496-9 · Cited by 481 · see citing works
“, 1998), multiple sclerosis (Raine, 1997) and autoimmune encephalitis, as well as a number of disorders such as cerebrovascular diseases (Becker, 1998) and Alzheimer’s disease (AD) (McGeer and McGeer, 1995; Neuroinflammation Working Group, 2000; Akiyama, 2000; Eikelenboom et al., 2000).”
BackgroundClinical manifestations of cerebral amyloid angiopathy–related inflammation
Eng, J. A., Frosch, M. P., Choi, K., Rebeck, G. W., & Greenberg, S. M. (2004) · Annals of Neurology · doi:10.1002/ana.10810 · Cited by 417 · see citing works
Noradrenergic mechanisms in neurodegenerative diseases: a theory
Marien, M. R., Colpaert, F. C., & Rosenquist, A. C. (2004) · Brain Research Reviews · doi:10.1016/j.brainresrev.2004.02.002 · Cited by 411 · see citing works
NSAIDs and Alzheimer disease: Epidemiological, animal model and clinical studies
McGeer, P. L., & McGeer, E. G. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.03.013 · Cited by 498 · see citing works
Self-citationThe molecular bases of Alzheimer’s disease and other neurodegenerative disorders
Maccioni, R. B., Muñoz, J. P., & Barbeito, L. (2001) · Archives of Medical Research · doi:10.1016/s0188-4409(01)00316-2 · Cited by 474 · see citing works
McGeer, P. L., Schwab, C., Parent, A., & Doudet, D. (2003) · Annals of Neurology · doi:10.1002/ana.10728 · Cited by 400 · see citing works
“Such a sparing is comparable with that observed for Alzheimer disease(25,26) where strong neuroinflammation has been documented.(27,28) PD cases have a higher frequency of the T allele for the IL-1 -511 regulatory region, which enhances expression of this inflammatory cytokine, than do controls.”
ResultSelf-citationPostoperative Impairment of Cognitive Function in Rats
Wan, Y., Xu, J., Ma, D., Zeng, Y., Cibelli, M., & Maze, M. (2007) · Anesthesiology · doi:10.1097/00000542-200703000-00007 · Cited by 394 · see citing works
Astrocyte phenotype in relation to Alzheimer‐type pathology in the ageing brain
Simpson, J. E., Ince, P. G., Lace, G., Forster, G., Shaw, P. J., Matthews, F., Savva, G., Brayne, C., & Wharton, S. B. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2008.05.015 · Cited by 381 · see citing works
Mandel, S. A., Weinreb, O., Amit, T., & Youdim, M. B. H. (2004) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.02291.x · Cited by 379 · see citing works
“…generation of ROS, thought to initiate the processes of OS and inflammatory cascade resulting in production of cytotoxic cytokines (TNFa, IL-1, and IL-6) in the microglia and in the surrounding neurons (Mogi et al. 1994; Blum-Degen et al. 1995; McGeer and McGeer 1995; Sakaguchi et al. 1996).”
BackgroundBastianetto, S., Ramassamy, C., Doré, S., Christen, Y., Poirier, J., & Quirion, R. (2000) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2000.00069.x · Cited by 378 · see citing works
Kurkowska‐Jastrzębska, I., Wrońska, A., Kohutnicka, M., Członkowski, A., & Członkowska, A. (1999) · Experimental Neurology · doi:10.1006/exnr.1998.6993 · Cited by 379 · see citing works
Blasko, I., Stampfer‐Kountchev, M., Robatscher, P., Veerhuis, R., Eikelenboom, P., & Grubeck‐Loebenstein, B. (2004) · Aging Cell · doi:10.1111/j.1474-9728.2004.00101.x · Cited by 374 · see citing works
“Following activation, astrocytes can release cytokines and growth factors similar to those produced by microglia (McGeer & McGeer, 1995), but can also produce trophic sub- stances such as nerve growth factor (NGF) (Aguado et al., 1998), the neurotrophic signalling molecule S100β (Mrak & Griffin,…”
BackgroundZhao, J. J., O’Connor, T., & Vassar, R. J. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-150 · Cited by 370 · see citing works
“Excessive levels of these mediators are apt to induce neuronal damage through a variety of mechanisms in AD and other neurodegenerative disorders [20].”
BackgroundJoseph, J. A., Shukitt‐Hale, B., & Casadesús, G. (2005) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/81.1.313s · Cited by 368 · see citing works
Role of Redox Signaling in Neuroinflammation and Neurodegenerative Diseases
Hsieh, H., & Yang, C. (2013) · BioMed Research International · doi:10.1155/2013/484613 · Cited by 370 · see citing works
Inflammasomes in neuroinflammation and changes in brain function: a focused review
Singhal, G., Jaehne, E. J., Corrigan, F., Toben, C. G., & Baune, B. T. (2014) · Frontiers in Neuroscience · doi:10.3389/fnins.2014.00315 · Cited by 365 · see citing works
“Researchers have observed upregulation of the complement system in human brain during AD and other neurodegenerative diseases (McGeer and McGeer, 1995; Yasojima et al., 1999).”
BackgroundA Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease
Hampel, H., Caraci, F., Cuello, A. C., Caruso, G., Nisticò, R., Corbo, M., Baldacci, F., Toschi, N., Garaci, F., Chiesa, P. A., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00456 · Cited by 360 · see citing works
“In addition, rodent models of AD indicate the ability of astrocytes to uptake and clear Aβ in subjects bearing cerebral fibrillar aggregates and diffuse plaques (16, 17, 33, 86).”
BackgroundAlmanzar, G., Schwaiger, S., Jenewein, B., Keller, M., Herndler‐Brandstetter, D., Würzner, R., Schönitzer, D., & Grubeck‐Loebenstein, B. (2005) · Journal of Virology · doi:10.1128/jvi.79.6.3675-3683.2005 · Cited by 356 · see citing works
“Proinflammatory cytokines are now believed to exacerbate the functional pathology and disease course of age-related disorders such as Alzheimer’s disease and atherosclerosis (23, 24, 34).”
BackgroundJudith Miklossy, A. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-90 · Cited by 356 · see citing works
“Both the cellular and humoral components of the immune system reactions [48-53] and critical constituents of the classical and alternative complement pathways are associated with AD lesions [51,52,149].”
BackgroundFactors correlated with hypermetabolism in patients with amyotrophic lateral sclerosis
Desport, J., Preux, P., Magy, L., Boirie, Y., Vallat, J. M., Beaufrère, B., & Couratier, P. (2001) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/74.3.328 · Cited by 353 · see citing works
Combs, C. K., Johnson, D. E., Cannady, S. B., Lehman, T. M., & Landreth, G. E. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-03-00928.1999 · Cited by 349 · see citing works
“A variety of acute-phase proinflammatory proteins are also associated with the amyloid plaques (McGeer and Rogers, 1992; McGeer and McGeer, 1995).”
BackgroundNeuroinflammation: Implications for the Pathogenesis and Molecular Diagnosis of Alzheimer's Disease
Rojo, L. E., Fernández, J. A., Maccioni, A. A., Jimenez, J. M., & Maccioni, R. B. (2008) · Archives of Medical Research · doi:10.1016/j.arcmed.2007.10.001 · Cited by 351 · see citing works
“During the last 13 years, strong evidence has been published supporting the fact that the complement system, a major component of inflammatory responses, plays a pivotal role in AD, especially during early subclinical stages of the neurodegenerative process (106,107,113,122).”
BackgroundInfluentialAmyloidogenic role of cytokine TGF-β1 in transgenic mice and in Alzheimer's disease
Wyss-Coray, T., Masliah, E., Mallory, M., McConlogue, L., Johnson-Wood, K., Lin, C., & Mucke, L. (1997) · Nature · doi:10.1038/39321 · Cited by 417 · see citing works
“Indirect evidence has been accumulating that inflammatory mediators may be important in the progression of this and other neurodegenerative disease”
BackgroundCalderón‐Garcidueñas, L., Maronpot, R. R., Torres‐Jardón, R., Henríquez-Roldán, C. F., Schoonhoven, R., Acuña-Ayala, H., Villarreal-Calderón, A., Nakamura, J., Fernando, R. A., Reed, W., et al. (2003) · Toxicologic Pathology · doi:10.1080/01926230390226645 · Cited by 350 · see citing works
“APP levels are influenced by IL1 and IL6 (66, 92, 94) and are thought to be important contributors to the pathogenesis of Alzheimer’s disease (69, 73).”
BackgroundInterleukin-6 Covaries Inversely with Hippocampal Grey Matter Volume in Middle-Aged Adults
Marsland, A. L., Gianaros, P. J., Abramowitch, S. M., Manuck, S. B., & Hariri, A. R. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.04.016 · Cited by 348 · see citing works
“In particular, these syndromes have been associated with high levels of central and peripheral IL-1 and IL-6 (21-26), with IL-6 levels predicting subsequent cognitive decline among the elderly (24,26,27).”
BackgroundLiu, B., Du, L., & Hong, J.-S. (2000) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)39275-4 · Cited by 347 · see citing works
“It is well accepted that proinflammatory and cytotoxic factors produced by activated microglia contribute to neurodegeneration and that prevention of microglia activation serves to reduce neuronal injury (McGeer and McGeer, 1995; Epstein, 1998).”
Association of Microglia with Amyloid Plaques in Brains of APP23 Transgenic Mice
Stalder, M., Phinney, A., Probst, A., Sommer, B., Staufenbiel, M., & Jucker, M. (1999) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)65423-5 · Cited by 345 · see citing works
“–10 Activation of microglia is thought to induce an inflammatory response in the central nervous system and to be a mediator of the amyloid-associated neurodegeneration in AD brain.(11,12) The involvement of inflammation in the progress of AD is underlined by clinical studies showing an attenuation of AD symptoms by n…”
BackgroundWilms, H., Sievers, J., Rickert, U., Rostami‐Yazdi, M., Mrowietz, U., & Lucius, R. (2010) · Journal of Neuroinflammation · doi:10.1186/1742-2094-7-30 · Cited by 346 · see citing works
MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide
Schroeter, H., BOYD, C., SPENCER, J., WILLIAMS, R., Cadenas, E., & Rice-Evans, C. A. (2002) · Neurobiology of Aging · doi:10.1016/s0197-4580(02)00075-1 · Cited by 338 · see citing works
“Oxidative stress has been shown to contribute to the neuropathology of a number of neurodegenerative disorders [77], including Alzheimer’s disease [14], Parkinson’s disease[231] and Huntington’s disease [4], as well as being implicated in neuronal loss associated with age-related cognitive decline[64,161], cerebral is…”
BackgroundResveratrol—A boon for treating Alzheimer's disease?
Anekonda, T. S. (2006) · Brain Research Reviews · doi:10.1016/j.brainresrev.2006.04.004 · Cited by 338 · see citing works
“Aβ-induced inflammatory reaction involves the activation of both microglia and astroglia in many neurological disorders, including AD (McGeer and McGeer, 1995; Monsonego and Weiner, 2003).”
BackgroundBlood–Brain Barrier Pathology in Alzheimer's and Parkinson's Disease: Implications for Drug Therapy
Desai, B. S., Monahan, A. J., Carvey, P. M., & Hendey, B. (2007) · Cell Transplantation · doi:10.3727/000000007783464731 · Cited by 339 · see citing works
Wilms, H., Rosenstiel, P. C., Sievers, J., Deuschl, G., Zecca, L., & Lucius, R. (2003) · The FASEB Journal · doi:10.1096/fj.02-0314fje · Cited by 337 · see citing works
The importance of inflammatory mechanisms in alzheimer disease
McGeer, E. G., & McGeer, P. L. (1998) · Experimental Gerontology · doi:10.1016/s0531-5565(98)00013-8 · Cited by 335 · see citing works
Self-citation
- Authors
- MCGEER, P., & MCGEER, E.
- Affiliations
- University of British Columbia (CA)
- Corresponding author
- MCGEER, P
- Venue
- Brain Research Reviews
- Publisher
- Elsevier BV
- Published
- 1995-09
- Volume
- 21
- Issue
- 2
- Pages
- 195-218
- ISSN
- 0165-0173 (ISSN-L)
- OpenAlex
- W2090930997
- Cited by
- 1,287
- References
- 319
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 17 · 2023: 14 · 2022: 24 · 2021: 19 · 2020: 16 · 2019: 18 · 2018: 27 · 2017: 29 · 2016: 19 · 2015: 29 · 2014: 46 · 2013: 42 · 2012: 36
- FWCI
- 5.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Research Reviews (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer Society of B.C.
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- neuroinflammation, Alzheimer's disease, neurodegenerative diseases, microglia, astrocytes, complement system, inflammatory cytokines, acute phase proteins, chronic inflammation, anti-inflammatory therapy, indomethacin, anti-inflammatory agents, neuroprotection
- MeSH terms
- Alzheimer Disease, Brain, Humans, Inflammation, Nerve Degeneration, Nervous System Diseases
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