Cited by 1,287Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsTryptophan and brain disorders

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The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases

MCGEER, P, MCGEER, E·1995·Brain Research Reviews

DOI 10.1016/0165-0173(95)00011-9

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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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Ichiyama, T., Zhao, H., Catania, A. P., Furukawa, S., & Lipton, J. M. (1999) · Experimental Neurology · doi:10.1006/exnr.1999.7064 · Cited by 82
Extrahepatic synthesis of complement proteins in inflammation
Laufer, J. (2001) · Molecular Immunology · doi:10.1016/s0161-5890(01)00044-x · Cited by 81
Plasminogen activator inhibitor-1 as an early potential diagnostic marker for Alzheimer's disease
Oh, J.-H., Lee, H., Song, J., Park, S. I., & Kim, H. (2014) · Experimental Gerontology · doi:10.1016/j.exger.2014.10.004 · Cited by 82
Involvement of proinflammatory factors, apoptosis, caspase-3 activation and Ca2+ disturbance in microglia activation-mediated dopaminergic cell degeneration
Wang, X., Chen, S., Ma, G., Ye, M., & Lü, G. (2005) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2005.06.012 · Cited by 81
Non-steroidal Anti-inflammatory Drugs Stimulate Secretion of Non-amyloidogenic Precursor Protein
Avramovich‐Tirosh, Y., Amit, T., & Youdim, M. B. H. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201308200 · Cited by 86
Activated Microglial Cells Are Colocalized With Perivascular Deposits of Amyloid-β Protein in Alzheimer’s Disease Brain
Uchihara, T., Akiyama, H., Kondo, H., & Ikeda, K. (1997) · Stroke · doi:10.1161/01.str.28.10.1948 · Cited by 79
Doxycycline Reduces Cleaved Caspase-3 and Microglial Activation in An Animal Model of Neonatal Hypoxia-Ischemia
Jantzie, L. L., Cheung, P., & Todd, K. G. (2005) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600025 · Cited by 80
Different pathways for iNOS‐mediated toxicity in vitro dependent on neuronal maturation and NMDA receptor expression
Golde, S., Chandran, S., Brown, G. C., & Compston, A. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.00973.x · Cited by 77
“Anti-inflammatory treatments influence the progression of AD (McGeer and McGeer 1995; McGeer et al. 1996; Stewart et al. 1997; Lim et al. 2000), and modulation of the inflammatory response in multiple sclerosis may slow the rate of brain atrophy (Rudick et al. 1999; Zivadinov et al. 2001),…”
Background
Differential regulation of microglial activation by propentofylline via cAMP signaling
Si, Q., Nakamura, Y., Ogata, T., Kataoka, K., & Schubert, P. (1998) · Brain Research · doi:10.1016/s0006-8993(98)00954-8 · Cited by 79
NSAIDS inhibit the IL-1β-induced IL-6 release from human post-mortem astrocytes: the involvement of prostaglandin E2
Blom, M. A. A., van Twillert, M. G. H., de Vries, S. C., Engels, F., Finch, C. E., Veerhuis, R., & Eikelenboom, P. (1997) · Brain Research · doi:10.1016/s0006-8993(97)01204-3 · Cited by 79
Drugs targeting alzheimer’s disease: Some things old and some things new
Michaelis, M. L. (2003) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.102.035840 · Cited by 78
“Resident macrophages in brain, the microglia, are activated in the presence of A oligomers, triggering the complement cascade and release of cytokines that propagate the inflammatory response (McGeer and McGeer, 1995).”
Background
Tyrosine nitration of a synaptic protein synaptophysin contributes to amyloid β-peptide-induced cholinergic dysfunction
Tran, M. H., Yamada, K., Nakajima, A., Mizuno, M., He, J., Kamei, H., & Nabeshima, T. (2003) · Molecular Psychiatry · doi:10.1038/sj.mp.4001240 · Cited by 78
Sulfation of heparan sulfate associated with amyloid-β plaques in patients with Alzheimer’s disease
Bruinsma, I. B., Riet, L. T., Gevers, T. J. G., ten Dam, G. B., Kuppevelt, T. H. V., David, G., Küsters, B., de Waal, R. M. W., & Verbeek, M. M. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0577-1 · Cited by 78
“Aggregation of the amyloid-b (Ab) protein can be affected by many macromolecules, such as heat shock proteins [46], complement factors [ 22 ], apolipoprotein E (ApoE) [34], and proteoglycans [33].”
Background
Parkinson's disease: changes in apoptosis-related factors suggesting possible gene therapy
Nagatsu, T. (2002) · Journal of Neural Transmission · doi:10.1007/s007020200061 · Cited by 78
Neuroinflammation and Alzheimer Disease: Clinical and Therapeutic Implications
Eikelenboom, P., Rozemüller, A. J. M., Hoozemans, J. J. M., Veerhuis, R., & van Gool, W. A. (2000) · Alzheimer Disease & Associated Disorders · doi:10.1097/00002093-200000001-00009 · Cited by 78
“During the past 15 years, a variety of inflammatory proteins were reported to be associated the neuritic plaques (Eikelenboom et al, 1994; McGeer and McGeer, 1995).”
Background
Role of Antiproliferative B Cell Translocation Gene-1 as an Apoptotic Sensitizer in Activation-Induced Cell Death of Brain Microglia
Lee, H., Cha, S.-H., Lee, M., Cho, G. J., Choi, W. S., & Suk, K. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.11.5802 · Cited by 74
“There is now growing evidence that toxic mediators produced by activated microglial cells might be involved in the pathogenesis of various neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and HIV-associated dementia (3, 4, 52).”
Background
Antidepressants reduce neuroinflammatory responses and astroglial alpha‐synuclein accumulation in a transgenic mouse model of multiple system atrophy
Valera, E., Ubhi, K. K., Mante, M., Rockenstein, E. M., & Masliah, E. (2013) · Glia · doi:10.1002/glia.22610 · Cited by 79
Prenylflavones from Psoralea corylifolia Inhibit Nitric Oxide Synthase Expression through the Inhibition of I-.KAPPA.B-.ALPHA. Degradation in Activated Microglial Cells
Lee, M. H., Kim, J. Y., & Ryu, J. (2005) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.28.2253 · Cited by 77
Comparison of gene expression profiles in neuropathic and inflammatory pain.
Parkitna, J. M. R., Korostyński, M., Kamińska, D., Obara, I., Mika, J., Przewłocka, B., & Przewłocki, R. (2006) · PubMed · Cited by 77
Implication of Complement System and its Regulators in Alzheimers Disease
Kolev, M. V., Ruseva, M. M., Harris, C. L., Morgan, B. P., & Donev, R. (2009) · Current Neuropharmacology · doi:10.2174/157015909787602805 · Cited by 78
“Other complement activators, such as amyloid P, C-Reactive Protein (CRP) and Hageman factor, were found in AD lesions and their potential role for the progression of the disease has been reviewed elsewhere [31].”
Background
Alzheimer's Disease: Neuropathologic Findings and Recent Advances in Imaging
Norfray, J. F., & Provenzale, J. M. (2004) · American Journal of Roentgenology · doi:10.2214/ajr.182.1.1820003 · Cited by 79
Cognitive Function and Dental Care Utilization Among Community-Dwelling Older Adults
Wu, B., Plassman, B. L., Liang, J., & Liang, W. (2007) · American Journal of Public Health · doi:10.2105/ajph.2007.109934 · Cited by 76
Toxicity of human THP-1 monocytic cells towards neuron-like cells is reduced by non-steroidal anti-inflammatory drugs (NSAIDs)
Klegeris, A., Walker, D. G., & McGeer, P. L. (1999) · Neuropharmacology · doi:10.1016/s0028-3908(99)00014-3 · Cited by 75
Self-citation
Innate Immunity, Local Inflammation, and Degenerative Disease
McGeer, P. L., & McGeer, E. G. (2002) · Science of Aging Knowledge Environment · doi:10.1126/sageke.2002.29.re3 · Cited by 75
Self-citation
Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales
Clark, I. A., Atwood, C., Bowen, R. L., Paz-Filho, G., & Vissel, B. (2012) · Pharmacological Reviews · doi:10.1124/pr.112.005850 · Cited by 76
“It is encouraging that this web site notes Dr. Patrick McGeer, a long-time exponent of earlier approaches to minimizing brain inflammation (McGeer and McGeer, 1995), as a consultant.”
Background
The Presence of Isoaspartic Acid in β-Amyloid Plaques Indicates Plaque Age
Fonseca, M. I., Head, E., Velázquez, P., Cotman, C. W., & Tenner, A. J. (1999) · Experimental Neurology · doi:10.1006/exnr.1999.7058 · Cited by 75
The anti-inflammatory glycoprotein, CD200, restores neurogenesis and enhances amyloid phagocytosis in a mouse model of Alzheimer's disease
Varnum, M. M., Kiyota, T., Dixie, K. L. I., Ikezu, S., & Ikezu, T. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.07.027 · Cited by 77
“Its expression can be altered after activation by specific stimulations (Kalaria, 1999,McGeer, et al., 1993,McGeer and McGeer, 1995).”
Background
Update on Biomarkers For Amyloid Pathology in Alzheimer’s Disease
Ashton, N. J., Schöll, M., Heurling, K., Gkanatsiou, E., Portelius, E., Höglund, K., Brinkmalm, G., Hye, A., Blennow, K., & Zetterberg, H. (2018) · Biomarkers in Medicine · doi:10.2217/bmm-2017-0433 · Cited by 78
“leads to localised microglial activation, cytokine release, astrocytosis and a multi-protein inflammatory response [23, 24].”
Background
The Chemistry of Neurodegeneration: Kinetic Data and Their Implications
Pavlin, M., Repič, M., Vianello, R., & Mavri, J. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9284-1 · Cited by 75
Peripheral administration of novel anti-inflammatories can attenuate the effects of chronic inflammation within the CNS
Hauss‐Wegrzyniak, B., Willard, L. B., Soldato, P. D., Pepeu, G., & Wenk, G. L. (1999) · Brain Research · doi:10.1016/s0006-8993(98)01081-6 · Cited by 75
Cytokines and Neurotrophins Interact in Normal and Diseased States
Otten, U., März, P., Heese, K., Hock, C., KUNZ, D., & Rose‐John, S. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb05398.x · Cited by 75
Mechanisms of cell death in Alzheimer disease — immunopathology
McGeer, P. L., & McGeer, E. G. (1998) · Journal of neural transmission. Supplementum · doi:10.1007/978-3-7091-7508-8_15 · Cited by 73
Self-citation
Therapeutic opportunities in polyglutamine disease
Hughes, R. E., & Olson, J. M. (2001) · Nature Medicine · doi:10.1038/86486 · Cited by 75
“In contrast to astrocytes, which have a role in neuronal health maintenance, activated microglial cells may be harmful to neuron”
Complement System in Alzheimer’s Disease
Shah, A., Kishore, U., & Shastri, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413647 · Cited by 76
“Extracellular tau aggregates can bind to astrocytes, get internalised via an integrin αV/β1 receptor; the integrin signalling pathway causes NF-κB activation leading to the release of several pro-inflammatory cytokines and chemokines that converts astrocytes to an A1-like neurotoxic state [82,109,110].”
Background
Low energy laser light (632.8 nm) suppresses amyloid-β peptide-induced oxidative and inflammatory responses in astrocytes
Yang, X., Askarova, S., Sheng, W., Chen, J. K., Sun, A. Y., Sun, G. Y., Yao, G., & Lee, J. C. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.09.025 · Cited by 73
“…al., 2006; Bolmont et al., 2008; Koenigsknecht-Talboo et al., 2008; Yan et al., 2009) which have been shown to secrete many pro-inflammatory molecules, such as cytokines, chemokines, prostaglandins , complement proteins and complement inhibitors (McGeer and McGeer, 1995, 2001; Zhang et al., 2009).”
Purinergic mediated changes in Ca2+ mobilization and functional responses in microglia: Effects of low levels of ATP
McLarnon, J. G. (2005) · Journal of Neuroscience Research · doi:10.1002/jnr.20475 · Cited by 74

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)
DOI: 10.1016/0165-0173(95)00011-9
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Brain Research Reviews (publishedVersion)
PubMed (publishedVersion)
Funders: Alzheimer Society of B.C.
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases

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