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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Perini, G., Bianca, V. D., Politi, V., Valle, G. D., Prà, I. D., Rossi, F., & Armato, U. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20011797 · Cited by 155
“As previously mentioned, it has been suggested that in AD an inflammatory reaction, which does not involve the migration of blood cells, but only the local production of cytokines and other mediators by glial cells, contributes per se to tissue damage and to A formation (14, 16, 65).”
Background
IL-10 modulates depressive-like behavior
Mesquita, A. R., Correia‐Neves, M., Roque, S., Castro, A. G., Vieira, P., Pedrosa, J., Palha, J. A., & Sousa, N. (2008) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2008.02.004 · Cited by 159
Diseases of aging
Wick, G., Jansen‐Dürr, P., Berger, P., Blasko, I., & Grubeck‐Loebenstein, B. (2000) · Vaccine · doi:10.1016/s0264-410x(99)00489-2 · Cited by 152
Amyloid β-Induced Nerve Growth Factor Dysmetabolism in Alzheimer Disease
Bruno, M. A., León, W., Fragoso, G., Mushynski, W. E., Almazán, G., & Cuello, A. C. (2009) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181aed9e6 · Cited by 152
“Activation of microglia by aggregated AA is a central feature in the chronic inflammatory pathology in AD (22) anda direct indicator of an ongoing chronic inflammatory process.”
Background
Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study
Rodriguez‐Vieitez, E., Ni, R., Gulyás, B. Z., Tóth, M., Häggkvist, J., Halldin, C., Voytenko, L. P., Marutle, A., & Nordberg, A. K. (2015) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-015-3047-0 · Cited by 149
Induction of cyclo-oxygenase 2 in brains of patients with Downʼs syndrome and dementia of Alzheimer type
Oka, A., & Takashima, S. (1997) · Neuroreport · doi:10.1097/00001756-199703240-00020 · Cited by 149
Is there an association between peripheral immune markers and structural/functional neuroimaging findings?
Frodl, T., & Amico, F. (2013) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2012.12.013 · Cited by 150
Amyloid beta-induced glycogen synthase kinase 3β phosphorylated VDAC1 in Alzheimer's disease: Implications for synaptic dysfunction and neuronal damage
Reddy, P. H. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.06.012 · Cited by 147
Neuroprotective and anti-inflammatory effects of flavonoids isolated from Rhus verniciflua in neuronal HT22 and microglial BV2 cell lines
Cho, N., Choi, J. H., Yang, H., Jeong, E. J., Lee, K. Y., Kim, Y. C., & Sung, S. H. (2012) · Food and Chemical Toxicology · doi:10.1016/j.fct.2012.03.052 · Cited by 146
THE GENETICS AND MOLECULAR PATHOLOGY OF ALZHEIMER'S DISEASE
Selkoe, D. J. (2000) · Neurologic Clinics · doi:10.1016/s0733-8619(05)70232-2 · Cited by 146
Neuroinflammatory Signaling Upregulation in Alzheimer's Disease
Lukiw, W. J., & Bazan, N. G. (2000) · Neurochemical Research · doi:10.1023/a:1007627725251 · Cited by 146
“βA nucleation into insoluble complexes is thought to lie at the core of microglia recruitment and the proliferation of proinflammatory pathways (5,6,109).”
Background
Enhanced clearance of Aβ in brain by sustaining the plasmin proteolysis cascade
Jacobsen, J. S., Comery, T. A., Martone, R. L., Elokdah, H. M., Crandall, D. L., Oganesian, A., Aschmies, S., Kirksey, Y. M., Gonzales, C., Xu, J., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0710823105 · Cited by 146
“Of particular relevance, PAI-1 expression is increased in the vicinity of amyloid deposits in brain (11) and is elevated at sites of inflammatory response in AD patients (21).”
Background
Early astrocytosis in autosomal dominant Alzheimer’s disease measured in vivo by multi-tracer positron emission tomography
Schöll, M., Carter, S. F., Westman, E., Rodriguez‐Vieitez, E., Almkvist, O., Þórðardóttir, S., Wall, A. E., Graff, C., Långström, B., & Nordberg, A. K. (2015) · Scientific Reports · doi:10.1038/srep16404 · Cited by 153
Lifestyle-related factors in predementia and dementia syndromes
Solfrizzi, V., Capurso, C. A., D’Introno, A., Colacicco, A. M., Santamato, A., Ranieri, M., Fiore, P., Capurso, A., & Panza, F. (2007) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.8.1.133 · Cited by 155
Molecular mechanism of the relation of monoamine oxidase B and its inhibitors to Parkinson’s disease: possible implications of glial cells
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“in the substantia nigra (McGeer et al., 1988; McGeer and McGeer, 1995).”
Background
Multiple faces of dynamin-related protein 1 and its role in Alzheimer's disease pathogenesis
Kandimalla, R. J. L., & Reddy, P. H. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.12.018 · Cited by 148
Glutamate release from microglia via glutamate transporter is enhanced by amyloid-beta peptide
Noda, M., Nakanishi, H., & Akaike, N. (1999) · Neuroscience · doi:10.1016/s0306-4522(99)00036-6 · Cited by 144
IL-4-Induced Selective Clearance of Oligomeric β-Amyloid Peptide1–42 by Rat Primary Type 2 Microglia
Shimizu, E., Kawahara, K., Kajizono, M., Sawada, M., & Nakayama, H. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.9.6503 · Cited by 143
“kines TNF- , IFN- , and IL-1 , as well as NO (4, 6).”
Background
In Vivo Positron Emission Tomographic Imaging of Glial Responses to Amyloid-β and Tau Pathologies in Mouse Models of Alzheimer's Disease and Related Disorders
Maeda, J., Zhang, M.-R., Okauchi, T., Ji, B., Ono, M., Hattori, S., Kumata, K., Iwata, N., Saido, T. C., Trojanowski, J. Q., et al. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.3076-10.2011 · Cited by 136
“It is well known that amyloid deposition triggers microglial and astroglial activation in AD brains (McGeer and McGeer, 1995).”
Background
Non-Cholinergic Strategies for Treating and Preventing Alzheimer??s Disease
Doraiswamy, P. M. (2002) · CNS Drugs · doi:10.2165/00023210-200216120-00003 · Cited by 142
Updating the mild encephalitis hypothesis of schizophrenia
Bechter, K. (2012) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2012.06.019 · Cited by 146
The effects of a novel NSAID on chronic neuroinflammation are age dependent☆
Hauss‐Wegrzyniak, B., Vraniak, P., & Wenk, G. L. (1999) · Neurobiology of Aging · doi:10.1016/s0197-4580(99)00028-7 · Cited by 141
Nonsteroidal anti‐inflammatory drugs and risk of Parkinson's disease
Ton, T. G. N., Heckbert, S. R., Longstreth, W. T., Jr., Rossing, M. A., Kukull, W. A., Franklin, G. M., Swanson, P. D., Smith‐Weller, T., & Checkoway, H. (2006) · Movement Disorders · doi:10.1002/mds.20856 · Cited by 141
Learning Decreases Aβ*56 and Tau Pathology and Ameliorates Behavioral Decline in 3xTg-AD Mice
Billings, L. M., Green, K. N., McGaugh, J. L., & LaFerla, F. M. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.4800-06.2007 · Cited by 145
“Inflammation has been associated previously with cognitive impairments (McGeer and McGeer, 1995, 1998); therefore, this decrease in activated microglia may account, in part, for the preserved cognitive phenotype observed in the experienced group.”
Background
Biochemistry and Molecular Biology of Amyloid β‐Protein and the Mechanism of Alzheimer's Disease
(2008) · Handbook of Clinical Neurology · doi:10.1016/s0072-9752(07)01223-7 · Cited by 137
Ibuprofen protects dopaminergic neurons against glutamate toxicity in vitro
Casper, D., Yaparpalvi, U., Rempel, N., & Werner, P. (2000) · Neuroscience Letters · doi:10.1016/s0304-3940(00)01294-5 · Cited by 138
Positron Emission Tomography Imaging of Neuroinflammation
Cagnin, A., Kassiou, M., Meikle, S. R., & Banati, R. B. (2007) · Neurotherapeutics · doi:10.1016/j.nurt.2007.04.006 · Cited by 137
“There have been consistent observations of activated microglia in primarily noninﬂammatory neurodegenerative diseases, such (among others) AD and PD. 43 It is experimentally well established that neuronal injury per se, in the absence of any other contributing pathology (such as damage to blood vessels), evokes a rapi…”
Influential
Trimethyltin-induced hippocampal degeneration as a tool to investigate neurodegenerative processes
Geloso, M. C., Corvino, V., & Michetti, F. (2011) · Neurochemistry International · doi:10.1016/j.neuint.2011.03.009 · Cited by 137
Oxidative Stress and Inflammation in Brain Aging: Nutritional Considerations
Joseph, J. A., Shukitt‐Hale, B., Casadesús, G., & Fisher, D. (2005) · Neurochemical Research · doi:10.1007/s11064-005-6967-4 · Cited by 137
“As an example, increased glial fibrillary acid protein expression is observed by middle age (32), and in the elderly this increase even occurs in the absence of a defined stimulus (33).”
Background
C-reactive protein is related to memory and medial temporal brain volume in older adults
Bettcher, B. M., Wilheim, R., Rigby, T., Green, R., Miller, J. W., Racine, C. A., Yaffe, K. S., Miller, B. L., & Kramer, J. H. (2011) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2011.07.240 · Cited by 147
“Early postmortem evaluations of Alzheimer’s disease patients identified increased inflammatory markers, including CRP, in the brain (McGeer and McGeer, 1995), as well as immunoreactivity of CRP in neurofibrillary tangles (Duong et al.”
Background
Melatonin in Alzheimer’s Disease: A Latent Endogenous Regulator of Neurogenesis to Mitigate Alzheimer’s Neuropathology
Hossain, M. F., Uddin, M. S., Uddin, G. M. S., Sumsuzzman, D. M., Islam, M. S., Barreto, G. E., Mathew, B., & Ashraf, G. M. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-01660-3 · Cited by 136
Both Sp1 and Sp3 are responsible for p21waf1 promoter activity induced by histone deacetylase inhibitor in NIH3T3 cells
Xiao, H., Hasegawa, T., & Isobe, K. (1999) · Journal of Cellular Biochemistry · doi:10.1002/(sici)1097-4644(19990601)73:3 · Cited by 131
Minocycline prevents neurotoxicity induced by cerebrospinal fluid from patients with motor neurone disease
Tikka, T., Vartiainen, N. E., Goldsteins, G., Oja, S. S., Andersen, P. M., Marklund, S. L., & Koıstınaho, J. (2002) · Brain · doi:10.1093/brain/awf068 · Cited by 136
“…difference compared with cultures treated with CSF from control patients (P < 0.05); # signi®cant difference compared with cultures treated with MND CSF (P < 0.05). chronic neurodegenerative diseases, including MND (McGeer and McGeer, 1995; Hirano, 1996; Yrja Ènheikki et al., 1998, 1999).”
ResultInfluential
Inhibition of microglial activation by the herbal flavonoid baicalein attenuates inflammation-mediated degeneration of dopaminergic neurons
Li, F.-Q., Wang, T., Pei, Z., Liu, B., & Hong, J. (2004) · Journal of Neural Transmission · doi:10.1007/s00702-004-0213-0 · Cited by 135
“Another characteristics of microglia is their activation at a very early stage in response to injury ( McGeer and McGeer, 1995; Kreutzberg, 1996; Gehrmann et al., 1995; Giulian, 1999).”
Background
Causes of Alzheimer's disease.
Muñoz, D. G., & Feldman, H. (2000) · PubMed Central · Cited by 136
Neurons express proteins of the classical complement pathway in Alzheimer disease.
Terai, K., Walker, D., Mcgeer, E., & McGeer, P. (1997) · Brain Research · doi:10.1016/s0006-8993(97)00849-4 · Cited by 149
Self-citation
Decellularized brain matrix enhances macrophage polarization and functional improvements in rat spinal cord injury
Hong, J. Y., Seo, Y., Davaa, G., Kim, H., Kim, S. H., & Hyun, J. K. (2019) · Acta Biomaterialia · doi:10.1016/j.actbio.2019.11.012 · Cited by 134
Inflammatory cytokines TNFα, IL-1β, and IL-6 are induced in endotoxin- stimulated microglia through different signaling cascades
Ishijima, T., & Nakajima, K. (2021) · Science Progress · doi:10.1177/00368504211054985 · Cited by 142
Alterations on phosphodiesterase type 7 and 8 isozyme mRNA expression in Alzheimer’s disease brains examined by in situ hybridization
Pérez-Torres, S., Cortés, R., Tolnay, M., Probst, A., Palacios, J. M., & Mengod, G. (2003) · Experimental Neurology · doi:10.1016/s0014-4886(03)00042-6 · Cited by 134
“AD (McGeer et al., 1990; McGeer and McGeer, 1992, 1995 ).”
Cellular and Behavioral Effects of Stilbene Resveratrol Analogues: Implications for Reducing the Deleterious Effects of Aging
Joseph, J. A., Fisher, D. R., Cheng, V., Rimando, A. M., & Shukitt‐Hale, B. (2008) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf802279h · Cited by 133

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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