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The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases
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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“Despite not being modeled in the pathway enrichment analysis and the lack of reported evidence of their possible relationship with AD, these genes encode key products having relevant functions within the immune system, which seems to influence several neurodegenerative and mental diseases.57, 58”
From APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer’s disease (2016) · cites this paper as [57]
In the citing paper
“This activation and consequent neuroinflammation are substantially involved in the progression of neurodegenerative diseases (McGeer and McGeer, 1995)”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as McGeer and McGeer, 1995
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Microglia and Alzheimer’s disease
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“Following early epidemiological evidence that chronic use of nonsteroidal anti-inflammatory drugs (NSAIDS) was associated with a decreased risk of developing AD (McGeer and McGeer, 1995), the use of anti-inflammatory agents in the treatment of AD has been intensely studied.”
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“14 COX-1 and COX-2, leading to the suppression of prostaglandin synthesis and chronic neuroinflammation contributing to the protracted degenerative course of AD (McGeer and McGeer, 1995; Akiyama et al., 2000).”
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“Activated microglia and mediators (cytokines, complement factors and acute phase reactants) are indeed commonly found to be closely associated to degenerating neurons (McGeer and McGeer 1995).”
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“IL-1, IL-6, Transforming Growth Factor (TGF)-b, LIF (Leukaemia Inhibitor Factor), MIF (Macrophage Inhibitor Factor), IL-10, IL-18 can be produced by the hypothalamus and/or pituitary glands (Breder et al., 1988 (Breder et al., , 1993 McGeer and McGeer, 1995; Maier and Watkins, 1998; Kronfol and Remick, 2000; Petrovsky…”
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“…release various cytokines, nitric oxide and reactive oxygen species, particularly when activated in a manner analogous to macrophage activation (see McGeer & McGeer, 1995) and, as such, are thought to play a role in various neurodegenerative diseases, including multiple sclerosis (Hofman et al.,…”
BackgroundBrain Renin–Angiotensin System at the Intersect of Physical and Cognitive Frailty
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“These products lead to an inflammatory response, microglial activation, and cytokine release, which then accelerates neuronal dysfunction and cognitive decline (Mcgeer and Mcgeer, 1995).”
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Aspirin and non-steroidal anti-inflammatory drugs inhibit amyloid-β aggregation
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“In recent years experimental data have accumulated indicating that a chronic in¯ammatory process is part of the pathology of Alzheimer's disease (AD) (McGeer & McGeer, 1995).”
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“…Is Activated by and Contributes to Neuroinflammation Chronic neuroinflammation has been shown to occur in Alzheimer’s disease (reviewed in: (McGeer and McGeer 1995; Akiyama et al. 2000; Bamberger and Landreth 2002; Wyss-Coray and Mucke 2002; Wyss-Coray 2006; Glass et al. 2010)) and in…”
Neuroinflammatory Signals in Alzheimer Disease and APP/PS1 Transgenic Mice
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“The CNS is not an exception to this process, as innate immune cells in the brain 2015 American Association of Neuropathologists, Inc.336 Copyright © 2015 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited. become more reactive with aging (67).”
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“Inflammation and innate immune reactions are involved in the pathology of several neurodegenerative diseases and traumatic brain injuries (McGeer and McGeer 1995; Morg- anti-Kossmann et al. 2002; Wyss-Coray and Mucke 2002).”
BackgroundGlutamate and the glutamate receptor system: a target for drug action
Bleich, S., R�mer, K., Wiltfang, J., & Kornhuber, J. (2003) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.933 · Cited by 125
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“In AD, microglia appear to cluster around Aβ plaques [105-107].”
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“Fibrillar β-amyloid deposits co-localize with numerous chronic inflammatory mediators and can activate the microglia in the brain (McGeer & McGeer, 1995).”
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BackgroundMinocycline prevents cholinergic loss in a mouse model of Down's syndrome
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“Fibrillar A stimulates TNF secretion only from postnatal microglia Because proinflammatory cytokines such as TNF are associated with plaques in AD (McGeer and McGeer, 1995), and previous data have demonstrated that A fibrils stimulate microglial TNF secretion in vitro (Meda et al.”
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“These results may be of relevance not only to ALS, but also to other neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, where the pathological role of protein aggregation in the disease mechanism remains elusive (Kawamata et al., 1992; McGeer and McGeer, 1995; Togo et al., 2001).”
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“…defects in cholinergic neurons; an age-dependent imbalance in hormones, and structural and functional changes in mitochondria (Terry et al., 1991; McGeer and McGeer, 1995; DeKosky et al., 1996; Nunomura et al., 2001; Reddy, 2006; Reddy and Beal, 2008; Du et al., 2010; Tampellini and Gouras,…”
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“An intense inflammatory reaction may produce autotoxicity in neurons, thus exacerbating the progression of AD and other nervous system diseases (McGeer and McGeer, 1995; Figure 3).”
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“Astrogliosis has been documented in postmortem tissue from individuals with AD [8,33], prion diseases [58], and other neural diseases.”
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“Microglial activation is a prominent feature of AD [1, 36, 47].”
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“Chronic inflammatory processes seem to be present in the AD brain, as shown by the activated microglia and the immunereactive associated protein [25].”
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“Several lines of evidence suggest that neurodegeneration observed in AD is due in part to microglial activation and the induction of inflammatory response genes at sites of pathology (Akiyama, 1994; Kalehua et al., 2000; McGeer and McGeer, 1995; Rogers et al., 1988).”
BackgroundRole of the Immune System in the Pathogenesis, Prevention and Treatment of Alzheimer??s Disease
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“[13,14] Following activation, microglial cells also produce acute-phase proteins, complement components, prostaglandins and cytokines.”
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In vivo imaging of neuroinflammation
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“Inflammation has long been noticed in the brains of patients with neurodegenerative disorders, including Parkinson's disease (PD) and Alzheimer's disease (AD) (McGeer & McGeer, 1995).”
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“Microglia are immunocompetent cells of central nervous system (CNS), which are activated in response to injury and diseases, and adopt a phagocytic and cytokine secreting phenotype [1–4].”
BackgroundExpression of mutant alpha-synuclein modulates microglial phenotype in vitro
Rojanathammanee, L., Murphy, E. J., & Combs, C. K. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-44 · Cited by 106
“A number of chronic neurodegenerative diseases, including Parkinson’s disease (PD), Alzheimer’s disease, and multiple sclerosis display an apparently aberrant microglial behavior that is hypothesized to contribute to disease progression [6-8].”
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“Neuroinflammation in PD PD, Alzheimer’s disease, and other neurodegenerative diseases are accompanied by neuroinflammation by activated microglia (Hirsch et al. 2012; McGeer et al. 1988; McGeer and McGeer 1995; Nagatsu and Sawada 2005; Sawada et al. 2007; Tansey and Goldberg 2010).”
BackgroundNilsson, S. E., Johansson, B., Takkinen, S., Zarit, S., McClearn, G., Melander, A., & Berg, S. (2003) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-003-0618-y · Cited by 104
“Alzheimer’s disease may at least in part be secondary to inflammatory processes in cognitive brain centres, the microglia being of central importance [18].”
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“In addition to indirect neuronal injury triggered by neurotoxic molecules released from HIV-infected or -activated macrophages and microglia [140-144], HIV Env directly triggers apoptosis of both primary rodent and human neurons [81,145-150] and astrocytes [151-153] and is probably a cause of CNS injury in AIDS [81,15…”
BackgroundActivation of microglia and chemokines in light-induced retinal degeneration.
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“Inflammation in the brain caused by activated microglia is a prominent pathological feature associated with the neurodegeneration caused by several diseases, including PD, AD, MS and amyotrophic lateral sclerosis (McGeer and McGeer, 1995; McGeer et al., 2001; Liu and Hong, 2003).”
BackgroundLee, Y. W., Cho, H. J., Lee, W. H., & Sonntag, W. E. (2012) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2012.20.4.357 · Cited by 103
“Furthermore, treatment with antioxidant compounds or non-steroidal anti-infl ammatory drugs (NSAIDs) exhibited benefi cial effects such as delaying the onset or slowing the progression of neurodegenerative diseases including AD and PD (McGeer and McGeer, 1995; Akiyama et al., 2000).”
BackgroundPromising Metabolite Profiles in the Plasma and CSF of Early Clinical Parkinson's Disease
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“PAF is known for its contribution to inflammatory responses in the brain (Bazan, 2006) and elevated levels are associated with the central nervous system pathophysiology (McGeer and McGeer, 1995).”
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“This chronic neuroinflammation causes the loss of white and grey matter that leads to functional deficits [6,7] that characterize the pathology of neurodegenerative diseases [8,9], stroke [10], and traumatic brain injuries [11].”
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“The extensive astrocytosis and microglial activation observed in the cerebral cortex of CJD patients as well as in animal models of TSEs support the hypothesis that inflammation, driven by activated glial cells, may participate to the pathogenesis of CJD, as in other chronic neurodegenerative diseases ( 60 ,61).”
BackgroundHuperzine A and tacrine attenuate ?-amyloid peptide-induced oxidative injury
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Mast Cell Tryptase Induces Microglia Activation via Protease-activated Receptor 2 Signaling
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BackgroundTransgenic mouse models of Alzheimer’s disease
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Lipid Signaling and Synaptic Plasticity
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“…implicated in synaptic signaling, and in traumatic brain injury, stroke, and certain neurologic disorders such as epilepsy and Alzheimer’s disease (McGeer and McGeer 1995; Miettinen and others 1997; Nakayama and others 1998; Ho and others 1999; Hewett and others 2000; Iadecola and others 2001;…”
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“Discussion Although it has long been known that activated microglia are associated with compact A β plaques”
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Metadata
- 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)
- 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
- 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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