Activation of Human Macrophages by Amyloid-β Is Attenuated by Astrocytes

Abstract

In Alzheimer’s disease, neuritic amyloid-β 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-β 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-β1–42 stimulate these macrophages to the production of superoxide anions and TNF-α. In contrast, astrocytes do not produce both inflammatory mediators when stimulated with amyloid-β1–42. In cocultures with astrocytes and amyloid-β1–42-stimulated macrophages, decreased levels of both superoxide anion and TNF-α were detected. These decreased levels of potential neurotoxins were due to binding of amyloid-β1–42 to astrocytes since FACScan analysis demonstrated binding of FITC-labeled amyloid-β1–42 to astrocytoma cells and pretreatment of astrocytes with amyloid-β1–16 prevented the decrease of superoxide anion in cocultures of human astrocytes and amyloid-β1–42-stimulated macrophages. To elucidate an intracellular pathway involved in TNF-α secretion, the activation state of NF-κB was investigated in macrophages and astrocytoma cells after amyloid-β1–42 treatment. Interestingly, although activation of NF-κB could not be detected in amyloid-β-stimulated macrophages, it was readily detected in astrocytoma cells. These results not only demonstrate that amyloid-β stimulation of astrocytes and macrophages result in different intracellular pathway activation but also indicate that astrocytes attenuate the immune response of macrophages to amyloid-β1–42 by interfering with amyloid-β1–42 binding to macrophages.