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Is Attenuated by Astrocytes1
*
Eijkman-Winkler Institute for Microbiology, Infectious Diseases and Inflammation, Section of Neuroimmunology, University Medical Center Utrecht, Utrecht, The Netherlands; and
Graduate School of Neurosciences Amsterdam, Research Institute of Neurosciences, Vrije Universiteit, Faculty of Medicine, Department of Pharmacology, Amsterdam, The Netherlands
In Alzheimer’s disease, neuritic amyloid-
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- 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-1–42 stimulate these macrophages to the
production of superoxide anions and TNF-
. In contrast, astrocytes do
not produce both inflammatory mediators when stimulated with
amyloid-1–42. In cocultures with astrocytes and
amyloid-1–42-stimulated macrophages, decreased levels
of both superoxide anion and TNF- were detected. These decreased
levels of potential neurotoxins were due to binding of
amyloid-1–42 to astrocytes since FACScan analysis
demonstrated binding of FITC-labeled amyloid-1–42 to
astrocytoma cells and pretreatment of astrocytes with
amyloid-1–16 prevented the decrease of superoxide anion
in cocultures of human astrocytes and
amyloid-1–42-stimulated macrophages. To elucidate an
intracellular pathway involved in TNF- secretion, the activation
state of NF-
B was investigated in macrophages and astrocytoma cells
after amyloid-1–42 treatment. Interestingly, although
activation of NF-B could not be detected in amyloid--stimulated
macrophages, it was readily detected in astrocytoma cells. These
results not only demonstrate that amyloid- stimulation of astrocytes
and macrophages result in different intracellular pathway activation
but also indicate that astrocytes attenuate the immune response of
macrophages to amyloid-1–42 by interfering with
amyloid-1–42 binding to
macrophages.
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