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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Implication of novel bis-imidazopyridines for management of Alzheimer's disease and establishment of its role on protein phosphatase 2A activity in brain
Parekh, K. D., Dash, R. P., Pandya, A. N., Vasu, K. K., & Nivsarkar, M. (2013) · Journal of Pharmacy and Pharmacology · doi:10.1111/jphp.12149 · Cited by 24
“Microglia and astrocytes leads to the generation of beta-amyloid protein (Aβ), one of the main pathologic features of AD([3]) which causes the activation of many of the inflammatory components down the line.”
Background
A reassessment of the telomere hypothesis of senescence
Reddel, R. R. (1999) · BioEssays · doi:10.1002/(sici)1521-1878(199812)20:12 · Cited by 65
Constitutive and cytokine‐regulated expression of presenilin‐1 and presenilin‐2 genes in human neural cell lines
Satoh, & Kuroda (1999) · Neuropathology and Applied Neurobiology · doi:10.1046/j.1365-2990.1999.00209.x · Cited by 23
Presenilins, β-amyloid precursor protein and the molecular basis of Alzheimer's disease
Selkoe, D. J. (2001) · Clinical Neuroscience Research · doi:10.1016/s1566-2772(00)00016-5 · Cited by 24
Plasma α1-antichymotrypsin in Alzheimer’s disease; relationships with APOE genotypes
Scacchi, R., Ruggeri, M., Gambina, G., Martini, M. C., Ferrari, G., & Corbo, R. M. (2001) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00246-3 · Cited by 24
Indomethacin inhibits delayed DNA fragmentation of hippocampal CA1 pyramidal neurons after transient forebrain ischemia in gerbils
Kondo, F., Kondo, Y., Gómez‐Vargas, M., & Ogawa, N. (1998) · Brain Research · doi:10.1016/s0006-8993(98)00211-x · Cited by 24
Mesencephalic neuron death induced by congeners of nitrogen monoxide is prevented by the lazaroid U-83836E
Grasbon-Frodl, E. M., & Brundin, P. (1997) · Experimental Brain Research · doi:10.1007/bf02454149 · Cited by 24
“Since NO, released by activated glial cells, has been suggested to trigger neurodegenerative processes ( McGeer and McGeer 1995 ), our findings might have implications for the pathogenesis of Parkinson's disease.”
Background
Toxicity of inhaled agents after prolonged administration
Manatpon, P., & Kofke, W. A. (2017) · Journal of Clinical Monitoring and Computing · doi:10.1007/s10877-017-0077-0 · Cited by 23
Mind Gaps and Bone Snaps: Exploring the Connection Between Alzheimer’s Disease and Osteoporosis
Wang, H. S., Karnik, S. J., Margetts, T. J., Plotkin, L. I., Movilă, A., Fehrenbacher, J. C., Kacena, M. A., & Oblak, A. L. (2024) · Current Osteoporosis Reports · doi:10.1007/s11914-023-00851-1 · Cited by 24
Abnormalities of protein kinases in neurodegenerative diseases
Wagey, R. T. E., & Krieger, C. (1998) · Birkhäuser Basel eBooks · doi:10.1007/978-3-0348-8845-5_4 · Cited by 23
Lib, transcriptionally induced in senile plaque-associated astrocytes, promotes glial migration through extracellular matrix
Satoh, K., Hata, M., Shimizu, T., Yokota, H., Akatsu, H., Yamamoto, T., Kosaka, K., & Yamada, T. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.07.117 · Cited by 24
No association of the HLA-A2 allele with Alzheimer's disease
Goumidi, L., Lambert, J., Cottel, D., Amouyel, P., & Chartier‐Harlin, M. (2002) · Neuroscience Letters · doi:10.1016/s0304-3940(02)01057-1 · Cited by 23
Age and meloxicam attenuate the ischemia/reperfusion-induced down-regulation in the NMDA receptor genes
Montori, S., Dos-Anjos, S., Martínez‐Villayandre, B., Regueiro-Purriños, M. M., Gonzalo-Orden, J. M., Ruano, D., & Fernández‐López, A. (2010) · Neurochemistry International · doi:10.1016/j.neuint.2010.03.013 · Cited by 23
“As a reference of the inflammatory response, we used GFAP, an astrocyte marker, and CD11b, a marker for microglia and infiltrating myeloid cells (Kim and de Vellis, 2005; McGeer and McGeer, 1995; Yatsiv et al., 2005), since they are the more widely used markers to quantify differences in brain inflammation following I…”
Method
Evaluation of neurobehavioral and neuroinflammatory end-points in the post-exposure period in rats sub-acutely exposed to manganese
dos Santos, D. M., Batoréu, M. C. C., de Almeida, I. T., Randall, L. D., Mateus, M. L., Vanda, A., Ramos, R., Torres, M. E., Aschner, M., & dos Santos, A. P. M. (2013) · Toxicology · doi:10.1016/j.tox.2013.09.008 · Cited by 23
“Given that chronic inflammatory processes have a role in neurodegeneration (McGeer and McGeer, 1995), in particular manganism, the objectives of the present study were a) to determine in vivo, whether neuroinflammation and neurobehabioral alterations recede during the clearance phase of Mn; b) to…”
Background
Platelet-activating factor enhancement of calcium influx and interleukin-6 expression, but not production, in human microglia
Sattayaprasert, P., Choi, H. B., Chongthammakun, S., & McLarnon, J. G. (2005) · Journal of Neuroinflammation · doi:10.1186/1742-2094-2-11 · Cited by 23
CNS Delivery and Anti-Inflammatory Effects of Intranasally Administered Cyclosporine-A in Cationic Nanoformulations
Yadav, S. K., Pawar, G. N., Kulkarni, P. P., Ferris, C. F., & Amiji, M. M. (2018) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.118.254672 · Cited by 23
“The deleterious role of activated microglia together with mediators (cytokines, complement factors) under conditions of inflammation in the CNS is becoming more evident and is found to be closely associated with degenerating neurons (McGeer and McGeer, 1995).”
Background
Bombycis corpus extract prevents amyloid-β-induced cytotoxicity and protects superoxide dismutase activity in cultured rat astrocytes
Kim, H.-J., Lee, W.-H., Yoon, C., Jeong, J., Nam, K., Kim, H., Choo, Y., Lee, M. C., & Kim, C. (2001) · Pharmacological Research · doi:10.1006/phrs.2000.0746 · Cited by 23
Expression of complement messenger RNAs by human endothelial cells
Klegeris, A., Bissonnette, C. J., Dorovini‐Zis, K., & McGeer, P. L. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02253-8 · Cited by 23
Self-citation
Effects of tryptophan depletion and catecholamine depletion on immune parameters in patients with seasonal affective disorder in remission with light therapy
Stastny, J., Konstantinidis, A., Schwarz, M., Rosenthal, N. E., Vitouch, O., Kasper, S. F., & Neumeister, A. (2003) · Biological Psychiatry · doi:10.1016/s0006-3223(02)01453-1 · Cited by 23
“Further evidence for the role of cytokines in depression can be inferred from studies showing elevations in cytokine levels in autoimmune diseases, such as rheumatoid arthritis or multiple sclerosis, stroke, brain trauma, and Alzheimer’s disease (Maini et al 2000; McGeer and McGeer 1995; Thornton and Raz 1997).”
Background
Overview and perspective on the therapy of alzheimer's disease from a preclinical viewpoint
Pepeu, G. (2001) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/s0278-5846(01)00146-4 · Cited by 23
Does estrogen replacement therapy protect against Alzheimer's disease?
Paganini‐Hill, A. (1997) · Osteoporosis International · doi:10.1007/bf01674807 · Cited by 23
Neuroglial activation in the auditory cortex and medial geniculate body of salicylate-induced tinnitus rats.
Xia, C., Yin, M., Wu, C., Ji, Y., & Zhou, Y. (2020) · PubMed Central · Cited by 22
Bacterial lipopolysaccharide induces a dose-dependent activation of neuroglia and loss of basal forebrain cholinergic cells in the rat brain
Houdek, H. M., Larson, J., Watt, J. A., & Rosenberger, T. A. (2014) · Inflammation and Cell Signaling · doi:10.14800/ics.47 · Cited by 22
“An intense recruitment of phagocytically active brain macrophages induced by the high-dose infusion of LPS may cause bystander lysis([9]) through release of secretory products that damage healthy neurons [41] suggesting a causative role in the pathogenesis of neurologic disease and injury .”
Background
Monocyte chemoattractant protein-1 promoter polymorphism and plasma levels in alzheimer’s disease
Porcellini, E., Ianni, M., Carbone, I., Franceschi, M., & Licastro, F. (2013) · Immunity & Ageing · doi:10.1186/1742-4933-10-6 · Cited by 22
“Activated microglia has been reported to express a large number of beta chemokines including monocyte chemoattractant protein-1 (MCP-1) [13,14].”
Background
Src suppressed C kinase substrate regulates the lipopolysaccharide-induced TNF-α biosynthesis in rat astrocytes
Sun, L., Cheng, C., Liu, H., Shen, C. C., Xiao, F., Qin, J., Yang, J., & Shen, A. (2007) · Journal of Molecular Neuroscience · doi:10.1007/s12031-007-0003-x · Cited by 22
“This is of particular interest given the increasing number of reports that show a beneficial effect of anti-inflammatory drugs on the progression of AD (McGeer and McGeer 1995; Breitner 1996).”
Chronic intracerebroventricular infusion of lipopolysaccharide: effects of ibuprofen treatment and behavioural and histopathological correlates
Richardson, R. L., Kim, E.-M., Gardiner, T. A., & O‘Hare, E. (2005) · Behavioural Pharmacology · doi:10.1097/01.fbp.0000179278.03868.96 · Cited by 22
“complement proteins from C1q through to membrane attack complex C5b-9 (Eikelenboom et al., 1989; Griffin et al., 1989; McGeer et al., 1989a, 1993; Mandybur and Chuirazzi, 1990; Bauer et al., 1992; McGeer and McGeer, 1995; Webster et al., 1997).”
Background
Alzheimer's disease: Its diagnosis and pathogenesis
Kril, J. J., & Halliday, G. M. (2001) · International review of neurobiology · doi:10.1016/s0074-7742(01)48016-0 · Cited by 22
Deep Learning of Speech Data for Early Detection of Alzheimer’s Disease in the Elderly
Ahn, K., Cho, M., Kim, S., Lee, K. E., Song, Y., Yoo, S., Jeon, S. Y., Kim, J. L., Yoon, D. H., & Kong, H. (2023) · Bioengineering · doi:10.3390/bioengineering10091093 · Cited by 21
Microglial Transforming Growth Factor-β Signaling in Alzheimer’s Disease
Vidovic, N., & Spittau, B. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25063090 · Cited by 22
“Both cell types are capable of secreting cytokines, chemokines, and other soluble molecules that regulate inflammatory processes in the CNS [13,14].”
Background
Interactions between PPAR-α and inflammation-related cytokine genes on the development of Alzheimer's disease, observed by the Epistasis Project.
Heun, R., Kölsch, H., Ibrahim‐Verbaas, C. A., Combarros, O., Aulchenko, Y. S., Breteler, M. M. B., Schuur, M., van Duijn, C. M., Hammond, N., Belbin, O., et al. (2012) · PubMed Central · Cited by 21
No association between the HLA-A2 allele and Alzheimer disease
Small, G. W., Scott, W. K., Komo, S., Yamaoka, L. H., Farrer, L. A., Auerbach, S. H., Saunders, A. M., Roses, A. D., Haines, J. L., & Pericak‐Vance, M. A. (1999) · Neurogenetics · doi:10.1007/s100480050080 · Cited by 21
“Pathophysiological studies of AD implicate chronic inflammatory and immune mechanisms in the disease process [17].”
Background
Looking for novel ways to treat the hallmarks of Alzheimer's disease
Stewart, A. J., Fox, A. W., Morimoto, B. H., & Gozes, I. (2007) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.16.8.1183 · Cited by 21
Expression of Prostaglandin PGE 2 Receptors under Conditions of Aging and Stress and the Protective Effect of the EP2 Agonist Butaprost on Retinal Ischemia
Osborne, N. N., Li, G., Ji, D., da Costa, B. L. A., Fawcett, R. J., Kang, K. D., & Rittenhouse, K. D. (2009) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.08-3185 · Cited by 21
Facilitatory effect of aspirin on glutamate release from rat hippocampal nerve terminals: Involvement of protein kinase C pathway
Wang, S. (2005) · Neurochemistry International · doi:10.1016/j.neuint.2005.10.006 · Cited by 21
Inhibitory action of 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK 11195) on some mononuclear phagocyte functions
Klegeris, A., McGeer, E. G., & McGeer, P. L. (2000) · Biochemical Pharmacology · doi:10.1016/s0006-2952(00)00252-5 · Cited by 21
Self-citation
Toxin‐Induced Blood Vessel Inclusions Caused by the Chronic Administration of Aluminum and Sodium Fluoride and Their Implications for Dementiaa
Isaacson, R. L., Varner, J., & Jensen, K. F. (1997) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1997.tb48426.x · Cited by 21
Morphological, biochemical and behaviouralchanges induced by neurotoxic and inflammatory insultsto the nucleus basalis
Casamenti, F., Prosperi, C., Scali, C., Giovannelli, L., & Pepeu, G. (1998) · International Journal of Developmental Neuroscience · doi:10.1016/s0736-5748(98)00080-x · Cited by 21
Amyloid P immunoreactivity precedes C4d deposition on extracellular neurofibrillary tangles
Schwab, C., Steele, J. C., McGeer, E. G., & McGeer, P. L. (1996) · Acta Neuropathologica · doi:10.1007/s004010050586 · Cited by 21
“For example, activation of the immune system could lead to further autotoxic neuronal damage [ 21 ].”
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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