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

In Alzheimer's disease, neuritic amyloid-beta plaques along with surroundin g activated microglia and astrocytes are thought to play an important role in the inflammatory events leading to neurodegeneration. Studies have indic ated that amyloid-beta can be directly neurotoxic by activating these glial cells to produce oxygen radicals and proinflammatory cytokines. This repor t shows that, using primary human monocyte-derived macrophages as model cel ls for microglia, amyloid-beta (1-42) stimulate these macrophages to the pr oduction of superoxide anions and TNF-alpha. In contrast, astrocytes do not produce both inflammatory mediators when stimulated with amyloid-beta (1-4 2.) In cocultures with astrocytes and amyloid-beta (1-42)-stimulated macrop hages, decreased levels of both superoxide anion and TNF-alpha were detecte d, These decreased levels of potential neurotoxins were due to binding of a myloid-beta (1-42) to astrocytes since FACScan analysis demonstrated bindin g of FITC-labeled amyloid-beta (1-42) to astrocytoma cells and pretreatment of astrocytes with amyloid-beta (1-42) prevented the decrease of superoxid e anion in cocultures of human astrocytes and amyloid-beta (1-42)-stimulate d macrophages. To elucidate an intracellular pathway involved in TNF-a secr etion, the activation state of NF-ICB was investigated in macrophages and a strocytoma cells after amyloid-beta (1-42) treatment. Interestingly, althou gh activation of NF-kappaB could not be detected in amyloid-beta -stimulate d macrophages, it was readily detected in astrocytoma cells. These results not only demonstrate that amyloid-beta stimulation of astrocytes and macrop hages result in different intracellular pathway activation but also indicat e that astrocytes attenuate the immune response of macrophages to amyloid-b eta (1-42) by interfering with amyloid-beta (1-42) binding to macrophages.