title: A central role for astrocytes in the inflammatory response to beta-amyloid; chemokines, cytokines and reactive oxygen species are produced.
abstract: Alzheimer's disease (AD) is the commonest form of adult onset dementia and is characterised neuropathologically by the accumulation of plaques containing beta-amyloid (A beta) fibrils, reactive astrocytes, activated microglia, and leukocytes. A beta plays a role in the pathology of AD by directly causing neuronal cytotoxicity and stimulating microglia to secrete cytokines and reactive oxygen species (ROS) which also damage neurons. Here, we demonstrate that A beta activates astrocytes and oligodendrocytes (the most common cell types in the brain) to produce chemokines, in particular MCP-1 and RANTES, which serve as potent in vitro microglial and macrophage chemoattractants. Furthermore, we have shown that A beta activates astrocytes to upregulate pro-inflammatory cytokine expression and enhances the production of ROS. We propose therefore that A beta-mediated astrocyte activation initiates an inflammatory cascade which could be targeted for therapeutic intervention in AD.
authors.affiliation: British Biotech Pharmaceuticals, Oxford, UK. johnstonem@britbio.co.uk
authors.forename: M
authors.initials: M
authors.lastname: Johnstone
authors.forename: A J
authors.initials: AJ
authors.lastname: Gearing
authors.forename: K M
authors.initials: KM
authors.lastname: Miller
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000276:immunology* / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D001921:Brain / Q000166:cytology / Q000276:immunology; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology*; D018946:Chemokine CCL5 / Q000235:genetics / Q000276:immunology*; D054426:Chemokine CXCL2; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000235:genetics / Q000276:immunology; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology; D015870:Gene Expression / Q000276:immunology; D006131:Growth Inhibitors / Q000235:genetics / Q000276:immunology; D006133:Growth Substances / Q000235:genetics / Q000276:immunology; D036341:Intercellular Signaling Peptides and Proteins; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D015846:Monokines / Q000235:genetics / Q000276:immunology; D009443:Neuritis / Q000276:immunology; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D015345:Oligonucleotide Probes; D010446:Peptide Fragments / Q000276:immunology* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000276:immunology*
chemical_list: D016229:Amyloid beta-Peptides; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D054426:Chemokine CXCL2; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C513296:Cxcl2 protein, rat; D006131:Growth Inhibitors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D015846:Monokines; D015345:Oligonucleotide Probes; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C113041:amyloid beta-protein (35-25); C090308:amyloid beta-protein (40-1)