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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Hypoxia-Induced Neuroinflammation in Alzheimer’s Disease: Potential Neuroprotective Effects of Centella asiatica
Hambali, A., Kumar, J., Hashim, N. F. M., Maniam, S., Mehat, M. Z., Cheema, M. S., Mustapha, M., Adenan, M. I., Stanslas, J., & Hamid, H. A. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.712317 · Cited by 65
“Previous notion of immune-privileged CNS was partly due to the presence of blood–brain barrier (BBB), lack of lymphatic drainage and immune-incompetent microglia (Barker and Billingham, 1978; McGeer and McGeer, 1995; Carson et al., 2006a).”
Background
Suppression of activated microglia promotes survival and function of transplanted oligodendroglial progenitors
Zhang, S., Goetz, B. D., & Duncan, I. D. (2002) · Glia · doi:10.1002/glia.10172 · Cited by 60
Behavioural and histopathological analyses of ibuprofen treatment on the effect of aggregated Aβ(1–42) injections in the rat
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Mechanisms of the inhibitory effects of amyloid β-protein on synaptic plasticity
Rowan, M. J., Klyubin, I. V., Wang, Q., & Anwyl, R. (2004) · Experimental Gerontology · doi:10.1016/j.exger.2004.06.020 · Cited by 60
Red wine micronutrients as protective agents in Alzheimer-like induced insult
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Stress proteins and glial functions: possible therapeutic targets for neurodegenerative disorders
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β-Ionone attenuates LPS-induced pro-inflammatory mediators such as NO, PGE2 and TNF-α in BV2 microglial cells via suppression of the NF-κB and MAPK pathway
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Minocycline modulates neuroprotective effect of hesperidin against quinolinic acid induced Huntington's disease like symptoms in rats: Behavioral, biochemical, cellular and histological evidences
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Type 2 diabetes mellitus in the pathophysiology of Alzheimer's disease
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Expression of presenilin-1 and -2 mRNAs in rat and Alzheimer's disease brains
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Self-citation
Neurotoxic consequences of central long-term administration of interleukin-2 in rats
Hanisch, U., Neuhaus, J., Rowe, W. B., van Rossum, D., Möller, T., Kettenmann, H., & Quirion, R. (1997) · Neuroscience · doi:10.1016/s0306-4522(97)00040-7 · Cited by 59
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“On the other hand, increased IL-6 levels have been found in autoimmune disorders affecting the brain, such as multiple sclerosis (McGeer & McGeer, 1995; Navikaset al., 1996).”
Background
Nerve Growth Factor
Skaper, S. D. (2001) · Molecular Neurobiology · doi:10.1385/mn:24:1-3:183 · Cited by 60
“The endogenous immuneresponse system of the brain may also participate in exacerbating the fundamental pathology of Alzheimer’s disease, apparently without stimulation by peripheral inflammatory mediators or the peripheral immune system (133).”
Background
Regulation of glutamate in cultures of human monocytic THP-1 and astrocytoma U-373 MG cells
Klegeris, A., Walker, D. G., & McGeer, P. L. (1997) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(97)00094-5 · Cited by 56
Self-citation
Tooth Loss May Predict Poor Cognitive Function in Community-Dwelling Adults without Dementia or Stroke: The PRESENT Project
Park, H., Suk, S., Cheong, J.-S., Lee, H., Chang, H. W., Do, S.-Y., & Kang, J.-S. (2013) · Journal of Korean Medical Science · doi:10.3346/jkms.2013.28.10.1518 · Cited by 58
“According to many studies, although inflammation is not an initiator of AD, inflammatory processes play a pivotal role in modulating the neuropathology of AD (5, 10, 11, 15, 16).”
Background
β-amyloid deposits in transgenic mice expressing human β-amyloid precursor protein have the same characteristics as those in Alzheimer's disease
Terai, K., Iwai, A., Kawabata, S., Tasaki, Y., Watanabe, T., Miyata, K., & Yamaguchi, T. (2001) · Neuroscience · doi:10.1016/s0306-4522(01)00095-1 · Cited by 58
Complement regulators C1 inhibitor and CD59 do not significantly inhibit complement activation in Alzheimer disease
Yasojima, K., McGeer, E. G., & McGeer, P. L. (1999) · Brain Research · doi:10.1016/s0006-8993(99)01514-0 · Cited by 58
Self-citation
Expression of prostaglandin E synthase mRNA is induced in beta-amyloid treated rat astrocytes
Satoh, K., Nagano, Y., Shimomura, C., Suzuki, N., Saeki, Y., & Yokota, H. (2000) · Neuroscience Letters · doi:10.1016/s0304-3940(00)00926-5 · Cited by 58
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“In the brains of patients with neurodegenerative diseases, activated microglia and astrocytes are capable of producing a whole variety of proinflammatory mediators [ 26 , 31], which may raise the inflammatory level of brain parenchyma and activate these vascular cells.”
BackgroundInfluential
Brain inflammatory reaction in an animal model of neuronal degeneration and its modulation by an anti‐inflammatory drug: implication in Alzheimer's disease
Scali, C., Prosperi, C., Vannucchi, M. G., Pepeu, G., & Casamenti, F. (2000) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2000.00075.x · Cited by 58
Apoptosis, Neurotrophic Factors and Neurodegeneration
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A Heme Oxygenase-1 Transducer Model of Degenerative and Developmental Brain Disorders
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“Likely sources of enhanced OS in the AD brain include production of reactive oxygen species (ROS) by senescent mitochondria, accelerated β-amyloid deposition [10], elaboration of tumor necrosis factor-α (TNFα), interleukin-1 β (IL-1β) and nitric oxide (NO) by activated microglia [11] and excessive sequestration of non…”
Background
Differential distribution of PDE4D splice variant mRNAs in rat brain suggests association with specific pathways and presynaptical localization
Miró, X., Pérez-Torres, S., Puigdomènech, P., Palacios, J. M., & Mengod, G. (2002) · Synapse · doi:10.1002/syn.10100 · Cited by 57
“Also described is a reduction of neuronal damage by rolipram following cerebral ischemia in the gerbil (Kato et al., 1995) and in Alzheimer’s disease (McGeer et al., 1990; McGeer and McGeer, 1995).”
IL-6 mediated alterations on immobile behavior of rats in the forced swim test via ERK1/2 activation in specific brain regions
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Lithostathine and pancreatitis-associated protein are involved in the very early stages of Alzheimer's disease
Duplan, L. (2001) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00182-2 · Cited by 57
“This hypothesis has recently received strong support from epidemiologic studies indicating that glucocorticoids or nonsteroidal anti-inflammatory drugs may be of help in preventing or delaying the occurrence of AD [5,8,34,38,44].”
Result
Emergence of endoplasmic reticulum stress and activated microglia in Purkinje cell degeneration mice
Kyuhou, S.-I., Kato, N., & Gemba, H. (2005) · Neuroscience Letters · doi:10.1016/j.neulet.2005.11.023 · Cited by 57
Perivascular astrocytes within Alzheimerʼs disease plaques
Cullen, K. M. (1997) · Neuroreport · doi:10.1097/00001756-199705260-00033 · Cited by 57
Amyloid ox–tox transducers
Mattson, M. P., & Rydel, R. E. (1996) · Nature · doi:10.1038/382674a0 · Cited by 57
Nitric Oxide Redox Species Exert Differential Permeability Effects on the Blood-Brain Barrier
Boje, K. M. K., & Lakhman, S. S. (2000) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)39267-5 · Cited by 59
“Many neurodegenerative diseases are accompanied by inflammation and permeability alterations in the blood-brain barrier (BBB) (Stewart, 1994; Claudio et al., 1995; McGeer and McGeer, 1995; Power and Johnson, 1995; Tomimoto et al., 1996; Zhang et al., 1996).”
The immune system as a system of relations
Daëron, M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.984678 · Cited by 60
Peripheral Inflammation and Cognitive Aging
Lim, A., Krajina, K., & Marsland, A. L. (2013) · Modern trends in psychiatry · doi:10.1159/000346362 · Cited by 57
Anti-inflammatory drugs and Alzheimer-type pathology in aging
Mackenzie, I. R. (2000) · Neurology · doi:10.1212/wnl.54.3.732 · Cited by 56
Amyloid β up‐regulates brain‐derived neurotrophic factor production from astrocytes: Rescue from amyloid β‐related neuritic degeneration
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Heme oxygenase-1 in Alzheimer disease: a tribute to Moussa Youdim
Schipper, H. M. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-010-0436-1 · Cited by 55
“Plausible sources of oxidative stress in the AD brain include accelerated b-amyloid deposition (Butterfield 2002), production of pro-inflammatory cytokines (TNFa, IL-1b) and nitric oxide (NO) by activated microglia ( McGeer and McGeer 1995 ), reactive oxygen species (ROS) generation by senescent mitochondria, and neur…”
Background
Protection of streptozotocin induced insulin receptor dysfunction, neuroinflammation and amyloidogenesis in astrocytes by insulin
Rajasekar, N., Dwivedi, S., Nath, C., Hanif, K., & Shukla, R. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.08.013 · Cited by 55
Non-steroidal anti-inflammatory drugs have potent anti-fibrillogenic and fibril-destabilizing effects for α-synuclein fibrils in vitro
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Immunohistochemical localization of plasminogen activator inhibitor-1 in rat and human brain tissues
Hino, H., Akiyama, H., Iseki, E., Kato, M., Kondo, H., Ikeda, K., & Kosaka, K. (2001) · Neuroscience Letters · doi:10.1016/s0304-3940(00)01679-7 · Cited by 55
Oxidative Stress and Neurodegeneration in Prion Diseases
Kim, J., Choi, S., Kim, N., Jin, J., Choi, E., Carp, R. I., & Kim, Y. (2001) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2001.tb05648.x · Cited by 55
Neurochemistry of Brain Neuroendocrine Immune System: Signal Molecules
Galoyan, A. A. (2000) · Neurochemical Research · doi:10.1023/a:1007656431612 · Cited by 55
“IL-2 is a neuroregulatory cytokine (71); cytokines including IL-2, participate in various pathologic states (72), namely in the pathogenesis of multiple sclerosis (72), at Alzheimer’s disease (73), in acute stress (74).”
Background
Degeneration process of Lewy bodies in the brains of patients with dementia with Lewy bodies using α-synuclein-immunohistochemistry
Iseki, E., Marui, W., Akiyama, H., Uéda, K., & Kosaka, K. (2000) · Neuroscience Letters · doi:10.1016/s0304-3940(00)01090-9 · Cited by 55

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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