title: Activation of human macrophages by amyloid-beta is attenuated by astrocytes.
abstract: In Alzheimer's disease, neuritic amyloid-beta plaques along with surrounding activated microglia and astrocytes are thought to play an important role in the inflammatory events leading to neurodegeneration. Studies have indicated that amyloid-beta can be directly neurotoxic by activating these glial cells to produce oxygen radicals and proinflammatory cytokines. This report shows that, using primary human monocyte-derived macrophages as model cells for microglia, amyloid-beta(1-42) stimulate these macrophages to the production of superoxide anions and TNF-alpha. In contrast, astrocytes do not produce both inflammatory mediators when stimulated with amyloid-beta(1-42). In cocultures with astrocytes and amyloid-beta(1-42)-stimulated macrophages, decreased levels of both superoxide anion and TNF-alpha were detected. These decreased levels of potential neurotoxins were due to binding of amyloid-beta(1-42) to astrocytes since FACScan analysis demonstrated binding of FITC-labeled amyloid-beta(1-42) to astrocytoma cells and pretreatment of astrocytes with amyloid-beta(1-16) prevented the decrease of superoxide anion in cocultures of human astrocytes and amyloid-beta(1-42)-stimulated macrophages. To elucidate an intracellular pathway involved in TNF-alpha secretion, the activation state of NF-kappaB was investigated in macrophages and astrocytoma cells after amyloid-beta(1-42) treatment. Interestingly, although activation of NF-kappaB could not be detected in amyloid-beta-stimulated macrophages, it was readily detected in astrocytoma cells. These results not only demonstrate that amyloid-beta stimulation of astrocytes and macrophages result in different intracellular pathway activation but also indicate that astrocytes attenuate the immune response of macrophages to amyloid-beta(1-42) by interfering with amyloid-beta(1-42) binding to macrophages.
authors.affiliation: Eijkman-Winkler Institute for Microbiology, Infectious Diseases and Inflammation, Section of Neuroimmunology, University Medical Center Utrecht, Room G04.614, Heidelberglaan 100, NL-3584 CX Utrecht, The Netherlands. h.a.smits@lab.azu.nl
authors.forename: H A
authors.initials: HA
authors.lastname: Smits
authors.forename: A J
authors.initials: AJ
authors.lastname: van Beelen
authors.forename: N M
authors.initials: NM
authors.lastname: de Vos
authors.forename: A
authors.initials: A
authors.lastname: Rijsmus
authors.forename: T
authors.initials: T
authors.lastname: van der Bruggen
authors.forename: J
authors.initials: J
authors.lastname: Verhoef
authors.forename: F L
authors.initials: FL
authors.lastname: van Muiswinkel
authors.forename: H S
authors.initials: HS
authors.lastname: Nottet
mesh_terms: D000328:Adult; D016229:Amyloid beta-Peptides / Q000276:immunology* / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D001254:Astrocytoma / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D006801:Humans; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000096:biosynthesis; D010446:Peptide Fragments / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016328:NF-kappa B; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42); D013481:Superoxides