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* Department of Neurology, Mannheim, University of Heidelberg, Germany;
Center of Molecular Biology, ZMBH, University of Heidelberg, Germany;
Department of Medical Chemistry, Szeged, Albert Szent Gyorgyi Medical University, Hungary; and
§ Department of Psychiatry, University of Bonn, Germany; and
German Cancer Research Center, Heidelberg, Germany
1Correspondence: Department of Neurology Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1–3, 68135 Mannheim, Germany. E-mail: Fass{at}neuro.ma.uni-heidelberg.de
Glial activation contiguous to deposits of amyloid peptide (Aß) is a
characteristic feature in Alzheimer’s disease. We performed
complementary in vitro and in vivo
experiments to study the extent, kinetics, and mechanisms of microglial
generation of nitric oxide (NO) induced by challenge with Aß. We
showed that Aß fibrils dose-dependently induced a marked release of
stable metabolites of NO in vivo that was strikingly
similar regarding extent and temporal profile to the one in the
parallel designed microglial cell culture experiments. However,
costimulation with interferon 
, which was a prerequisite for
Aß-induced NO generation in vitro, was not required
in vivo, demonstrating that factors are present in the
living brain that activate glial cells synergistically with Aß.
Therefore, in Alzheimer’s disease, deposits of Aß fibrils alone may
be sufficient to induce a chronic release of neurotoxic microglial
products, explaining the progressive neurodegeneration associated with
this disease. Our observation that systemic administration of selective
iNOS inhibitors abolishes Aß-induced NO generation in
vivo may have implications for therapy of Alzheimer’s
disease.—Ishii, K., Muelhauser, F., Liebl, U., Picard, M., Kühl,
S., Penke, B., Bayer, T., Wiessler, M., Hennerici, M., Beyreuther, K.,
Hartmann, T., Fassbender, K. Subacute NO generation induced by
Alzheimer’s ß-amyloid in the living brain: reversal by inhibition of
the inducible NO synthase.
Key Words: amyloid peptide • nitric oxide • iNOS • brain • in vivo microdialysis
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