Activation of human macrophages by amyloid-beta is attenuated by astrocytes

• Published in: The Journal of immunology (1950) 2001-06, Vol.166 (11), p.6869-6876
• Main Authors: Smits, H A, van Beelen, A J, de Vos, N M, Rijsmus, A, van der Bruggen, T, Verhoef, J, van Muiswinkel, F L, Nottet, H S
• Format: Article
• Language: English
• Subjects: Adult; Amyloid beta-Peptides - immunology; Amyloid beta-Peptides - pharmacology; Astrocytes - drug effects; Astrocytes - immunology; Astrocytes - metabolism; Astrocytoma - immunology; Astrocytoma - metabolism; Cell Communication - drug effects; Cell Communication - immunology; Cells, Cultured; Coculture Techniques; Humans; Macrophage Activation - drug effects; Macrophage Activation - immunology; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Microglia - drug effects; Microglia - immunology; Microglia - metabolism; NF-kappa B - biosynthesis; Peptide Fragments - pharmacology; Superoxides - metabolism; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.166.11.6869

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.