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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Essential Fatty Acids and the Brain
Haag, M. (2003) · The Canadian Journal of Psychiatry · doi:10.1177/070674370304800308 · Cited by 421
“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).”
Background
Occurrence 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
“, 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).”
Background
Clinical 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
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 425
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
Self-citation
The 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
Presence of reactive microglia in monkey substantia nigra years after 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine administration
McGeer, P. L., Schwab, C., Parent, A., & Doudet, D. (2003) · Annals of Neurology · doi:10.1002/ana.10728 · Cited by 400
“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-citation
Postoperative 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 397
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
Cell signaling pathways in the neuroprotective actions of the green tea polyphenol (‐)‐epigallocatechin‐3‐gallate: implications for neurodegenerative diseases
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 384
“…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).”
Background
The ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by β‐amyloid
Bastianetto, 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 383
The Inflammatory Reaction Following 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Intoxication in Mouse
Kurkowska‐Jastrzębska, I., Wrońska, A., Kohutnicka, M., Członkowski, A., & Członkowska, A. (1999) · Experimental Neurology · doi:10.1006/exnr.1998.6993 · Cited by 379
How chronic inflammation can affect the brain and support the development of Alzheimer's disease in old age: the role of microglia and astrocytes
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
“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,…”
Background
The contribution of activated astrocytes to Aβ production: Implications for Alzheimer's disease pathogenesis
Zhao, J. J., O’Connor, T., & Vassar, R. J. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-150 · Cited by 379
“Excessive levels of these mediators are apt to induce neuronal damage through a variety of mechanisms in AD and other neurodegenerative disorders [20].”
Background
Reversing the deleterious effects of aging on neuronal communication and behavior: beneficial properties of fruit polyphenolic compounds
Joseph, J. A., Shukitt‐Hale, B., & Casadesús, G. (2005) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/81.1.313s · Cited by 368
Role of Redox Signaling in Neuroinflammation and Neurodegenerative Diseases
Hsieh, H., & Yang, C. (2013) · BioMed Research International · doi:10.1155/2013/484613 · Cited by 372
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 372
“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).”
Background
A 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
“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).”
Background
Long-Term Cytomegalovirus Infection Leads to Significant Changes in the Composition of the CD8+T-Cell Repertoire, Which May Be the Basis for an Imbalance in the Cytokine Production Profile in Elderly Persons
Almanzar, 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
“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).”
Background
Alzheimer's disease - a neurospirochetosis. Analysis of the evidence following Koch's and Hill's criteria
Miklossy, J. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-90 · Cited by 358
“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].”
Background
Factors 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
Identification of Microglial Signal Transduction Pathways Mediating a Neurotoxic Response to Amyloidogenic Fragments of β-Amyloid and Prion Proteins
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
“A variety of acute-phase proinflammatory proteins are also associated with the amyloid plaques (McGeer and Rogers, 1992; McGeer and McGeer, 1995).”
Background
Neuroinflammation: 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
“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).”
BackgroundInfluential
Amyloidogenic 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
“Indirect evidence has been accumulating that inflammatory mediators may be important in the progression of this and other neurodegenerative disease”
Background
DNA Damage in Nasal and Brain Tissues of Canines Exposed to Air Pollutants Is Associated with Evidence of Chronic Brain Inflammation and Neurodegeneration
Calderón‐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 363
“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).”
Background
Interleukin-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
“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).”
Background
Naloxone Protects Rat Dopaminergic Neurons against Inflammatory Damage through Inhibition of Microglia Activation and Superoxide Generation
Liu, 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
“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
“–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…”
Background
Dimethylfumarate inhibits microglial and astrocytic inflammation by suppressing the synthesis of nitric oxide, IL-1β, TNF-α and IL-6 in an in-vitro model of brain inflammation
Wilms, 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 355
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
“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…”
Background
Resveratrol—A boon for treating Alzheimer's disease?
Anekonda, T. S. (2006) · Brain Research Reviews · doi:10.1016/j.brainresrev.2006.04.004 · Cited by 343
“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).”
Background
Blood–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
Activation of microglia by human neuromelanin is NF‐κB‐dependent and involves p38 mitogen‐activated protein kinase: implications for Parkinson's disease
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
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
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)
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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