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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Tanabe, K., Nakanishi, H., Maeda, H., Nishioku, T., Hashimoto, K., Liou, S., Akamine, A., & Yamamoto, K. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.22.15725 · Cited by 48
Kainic acid-induced activation of nuclear factor-κB in rat hippocampus
Matsuoka, Y., Kitamura, Y., Okazaki, M., Terai, K., & Taniguchi, T. (1999) · Experimental Brain Research · doi:10.1007/s002210050616 · Cited by 48
“These cytokines are regulated by intra- and inter-cellular signaling messengers in the CNS (Gehrmann et al. 1995; McGeer and McGeer 1995 ).”
Roles of Ca2+ and the Ca2+‐sensing receptor (CASR) in the expression of inducible NOS (nitric oxide synthase)‐2 and its BH4 (tetrahydrobiopterin)‐dependent activation in cytokine‐stimulated adult human astrocytes
Dal Pra, I., Chiarini, A., Nemeth, E. F., Armato, U., & Whitfield, J. F. (2005) · Journal of Cellular Biochemistry · doi:10.1002/jcb.20511 · Cited by 47
“…(ONOO ) that can harm and kill the neurons functionally and physically associated with the astrocytes [Ransom and Santheimer, 1992; Norenberg, 1994; McGeer and McGeer, 1995, 1999, 2003, 2004; Mrak et al., 1995; Dawson and Dawson, 1996; Hunot et al., 1996; Lincoln et al., 1997; Grzybicki et al.,…”
Background
The role of soluble intercellular adhesion molecules in neurodegenerative disorders
Rentzos, M., Michalopoulou, M., Nikolaou, C., Cambouri, C., Rombos, A., Dimitrakopoulos, A., & Vassilopoulos, D. (2005) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2004.11.001 · Cited by 45
“Presence of activated microglial cells has been demonstrated in pathological lesions in several neurological diseases like AD, Parkinson disease and multiple sclerosis [45,46].”
Background
Apoptotic cell death in neurons and glial cells: implications for Alzheimer's disease
Yoshihisa, K., Takashi, T., & Shun, S. (1999) · Japanese Journal of Pharmacology · doi:10.1254/jjp.79.1 · Cited by 47
Increases of kinin B1 and B2 receptors binding sites after brain infusion of amyloid-beta 1–40 peptide in rats
Viel, T. A., Caetano, A. L., Nasello, A. G., Lancelotti, C. L., Nunes, V. A., Araújo, M. S., & Buck, H. S. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.04.019 · Cited by 47
Relationship between neuropathology and disease progression in the SOD1G93A ALS mouse
Yang, W. W., Sidman, R. L., Taksir, T. V., Treleaven, C. M., Fidler, J. A., Cheng, S. H., Dodge, J. C., & Shihabuddin, L. S. (2010) · Experimental Neurology · doi:10.1016/j.expneurol.2010.11.019 · Cited by 51
“However, the influence of astroglia and microglia in ALS as well as other disorders of the CNS remained ambiguous as these cells purportedly could display both neuroprotective and neurotoxic activities (Hall et al., 1998; McGeer and McGeer, 1995; Minghetti and Levi, 1998; Sargsyan et al., 2005).”
Background
Inflammation and clinical presentation in neurodegenerative disease: a volatile relationship
Bettcher, B. M., & Kramer, J. H. (2012) · Neurocase · doi:10.1080/13554794.2011.654227 · Cited by 49
“control) in inflammatory markers, evaluating anti-inflammatory interventions, or delineating the molecular basis of inflammation ( Blasko et al, 2004 ; Glass, Saijo, Winner, Marchetto, & Gage, 2010 ; Gorelick, 2010 ; McGeer & McGeer, 1995 ; Wyss-Coray & Mucke, 2002 ), but instead will be directed towards elucidating c…”
Glycoprotein NMB: an Emerging Role in Neurodegenerative Disease
Budge, K. M., Neal, M. P., Richardson, J. R., & Safadi, F. F. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0707-z · Cited by 47
Inositol Phosphates and Phosphoinositides in Health and Disease
Shi, Y. H., Azab, A. N., Thompson, M. N., & Greenberg, M. L. (2006) · Springer eBooks · doi:10.1007/0-387-27600-9_11 · Cited by 46
Quantitative Volumetric Analyses of Brain Magnetic Resonance Imaging from Rat with Chronic Neuroinflammation
Hauss‐Wegrzyniak, B., Galons, J., & Wenk, G. L. (2000) · Experimental Neurology · doi:10.1006/exnr.2000.7469 · Cited by 47
Amyloid precursor protein beta-secretase (BACE) mRNA expression in human neural cell lines following induction of neuronal differentiation and exposure to cytokines and growth factors
Satoh, J., & Kuroda, Y. (2000) · Neuropathology · doi:10.1046/j.1440-1789.2000.00349.x · Cited by 47
Tumor necrosis factor α augments amyloid β protein (25–35) induced apoptosis in human cells
Blasko, I., Schmitt, T. L., Steiner, E., Trieb, K., & Grubeck‐Loebenstein, B. (1997) · Neuroscience Letters · doi:10.1016/s0304-3940(97)00845-8 · Cited by 47
Effects of S100B on Serotonergic Plasticity and Neuroinflammation in the Hippocampus in Down Syndrome and Alzheimer's Disease: Studies in an S100B Overexpressing Mouse Model
Shapiro, L. A., Bialowas‐McGoey, L. A., & Whitaker‐Azmitia, P. M. (2010) · Cardiovascular Psychiatry and Neurology · doi:10.1155/2010/153657 · Cited by 46
Hemorheological changes and overproduction of cytokines from immune cells in mild to moderate dementia of the Alzheimer’s type: adverse effects on cerebromicrovascular system.
Solerte, S. B., Ceresini, G., Ferrari, E., & Fioravanti, M. (2000) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00105-6 · Cited by 46
Mechanisms of Mitochondrial Malfunction in Alzheimer’s Disease: New Therapeutic Hope
Nabi, S. U., Khan, A., Siddiqui, E. M., Rehman, M. U., Alshahrani, S., Arafah, A. M., Mehan, S., Alsaffar, R. M., Alexiou, A. T., & Shen, B. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/4759963 · Cited by 51
Hydrogen peroxide increases gap junctional communication and induces astrocyte toxicity: Regulation by brain macrophages
Rouach, N., Calvo, C., Duquennoy, H., Glowinski, J., & Giaume, C. (2003) · Glia · doi:10.1002/glia.10300 · Cited by 45
Distribution patterns of cannabinoid CB1 receptors in the hippocampus of APPswe/PS1ΔE9 double transgenic mice
Kalifa, S., Polston, E. K., Allard, J. S., & Manaye, K. F. (2010) · Brain Research · doi:10.1016/j.brainres.2010.12.061 · Cited by 46
“…it is hypothesized that amyloid beta 42 (Aβ42) accumulation and diffuse plaque formation is associated with local microglial activation, cytokine release, reactive astrocytosis and a multiprotein inflammatory response (Eikelenboom et al, 1994; McGeer and McGeer, 1995 and Rogers et al., 1996).”
Misfolded tau protein and disease modifying pathways in transgenic rodent models of human tauopathies
Žilka, N., Korenova, M., & Novák, M. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0499-y · Cited by 47
“Multiple studies provide increasing amounts of evidence that neuroinflammation plays the fundamental role in the progression of AD and other non-AD tauopathies [104, 107, 108, 111].”
Oxidative metabolites are involved in polyamine-induced microglial cell death
Takano, K., Ogura, M., Yoneda, Y., & Nakamura, Y. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2005.05.014 · Cited by 45
Genetic background modifies neurodegeneration and neuroinflammation driven by misfolded human tau protein in rat model of tauopathy: implication for immunomodulatory approach to Alzheimer's disease
Stožická, Z., Žilka, N., Novák, P., Kováčech, B., Bugos, O., & Novák, M. (2010) · Journal of Neuroinflammation · doi:10.1186/1742-2094-7-64 · Cited by 46
“Neurofibrillary degeneration [25,26] and neuroinflammation [27-29] are prominent features of Alzheimer’s disease (AD) and related neurodegenerative disorders.”
Background
Effects of ATP and elevated K+ on K+ currents and intracellular Ca2+ in human microglia
McLarnon, J. G., Zhang, L., Goghari, V., Lee, Y. B., Walz, W., Krieger, C., & Kim, S. U. (1999) · Neuroscience · doi:10.1016/s0306-4522(98)00491-6 · Cited by 45
Fibroblast growth factor receptor-1 expression in the cortex and hippocampus in Alzheimer's disease
Takami, K., Matsuo, A., Terai, K., Walker, D. G., McGeer, E. G., & McGeer, P. L. (1998) · Brain Research · doi:10.1016/s0006-8993(98)00552-6 · Cited by 46
Self-citation
The role of complement in neurological and neuropsychiatric diseases
Morgan, B. P. (2015) · Expert Review of Clinical Immunology · doi:10.1586/1744666x.2015.1074039 · Cited by 44
Suppression of inducible nitric oxide synthase and cyclooxygenase-2 expression by tussilagone from farfarae flos in BV-2 microglial cells
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“These mediators are responsible for the brain injuries and neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease (McGeer and McGeer, 1995).”
Background
Neolignans from Piper kadsura and their anti-neuroinflammatory activity
Kim, K. H., Choi, J. W., Ha, S. K., Kim, S. Y., & Lee, K. R. (2009) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2009.10.016 · Cited by 44
Autotoxicity and Alzheimer Disease
McGeer, P. L., & McGeer, E. G. (2000) · Archives of Neurology · doi:10.1001/archneur.57.6.789 · Cited by 44
“Van Furth provided closure with his concept of the monocyte phagocytic system, through which all tissues are supplied with resident phagocytes from blood monocytes.(1) Highly activated microglia aggregate around the senile plaques and extracellular tangles of AD-affected brain.”
BackgroundMethodInfluentialSelf-citation
DNA Methylation Changes and Inflammaging in Aging-Associated Diseases
Alimohammadi, M., Makaremi, S., Rahimi, A. A. R., Asghariazar, V., Taghadosi, M., & Safarzadeh, E. (2022) · Epigenomics · doi:10.2217/epi-2022-0143 · Cited by 44
Alternative approaches for PET radiotracer development in Alzheimer's disease: imaging beyond plaque
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Deoxysappanone B, a homoisoflavone from the Chinese medicinal plant Caesalpinia sappan L., protects neurons from microglia-mediated inflammatory injuries via inhibition of IκB kinase (IKK)-NF-κB and p38/ERK MAPK pathways
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Control of the blood–brain barrier function in cancer cell metastasis
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“Beyond doubts, microglial activation is substantially involved in BBB impairments during the progression of neurodegenerative diseases, including Alzheimer ́s disease and multiple sclerosis (McGeer and McGeer, 1995; Dickstein et al., 2006; Zipser et al., 2007; Lassmann et al., 2012).”
Background
Association between genetic polymorphism of angiotensin-converting enzyme gene and Parkinson's disease
Lin, J.-J., Yueh, K.-C., Chang, D., & Lin, S. (2002) · Journal of the Neurological Sciences · doi:10.1016/s0022-510x(02)00081-3 · Cited by 43
A Novel Member of the Leucine-Rich Repeat Superfamily Induced in Rat Astrocytes by β-Amyloid
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Apolipoprotein E4 (ApoE4) but not ApoE3 or ApoE2 potentiates β-amyloid protein activation of complement in vitro
McGeer, P. L., Walker, D. G., Pitas, R. E., Mahley, R. W., & McGeer, E. G. (1997) · Brain Research · doi:10.1016/s0006-8993(96)01324-8 · Cited by 43
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HIV-Associated Dementia: New Insights into Disease Pathogenesis and Therapeutic Interventions
Swindells, S., Zheng, J., & Gendelman, H. E. (1999) · AIDS Patient Care and STDs · doi:10.1089/apc.1999.13.153 · Cited by 43
Bacterial Lipopolysaccharide Increases Prostaglandin Production by Rat Astrocytes via Inducible Cyclo-oxygenase: Evidence for the Involvement of Nuclear Factor κB
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Point Mutations in Aβ Result in the Formation of Distinct Polymorphic Aggregates in the Presence of Lipid Bilayers
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“intimately associated with dystrophic dendrites and axons, activated microglia, and reactive astrocytes [3].”
Background
Beneficial effects of berry fruit polyphenols on neuronal and behavioral aging
Lau, F. C., Shukitt‐Hale, B., & Joseph, J. A. (2006) · Journal of the Science of Food and Agriculture · doi:10.1002/jsfa.2671 · Cited by 42

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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