Subacute NO generation induced by Alzheimer's beta-amyloid in the living brain: reversal by inhibition of the inducible NO synthase

Glial activation contiguous to deposits of amyloid peptide (A beta) is a ch aracteristic 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 A beta. We showed that A beta fibrils dose-dependently induced a marked relea se of stable metabolites of NO in vivo that was strikingly similar regardin g extent and temporal profile to the one in the parallel designed microglia l cell culture experiments. However, costimulation with interferon gamma, w hich was a prerequisite for A beta-induced NO generation in vitro, was not required in vivo, demonstrating that factors are present in the living brai n that activate glial cells synergistically with A beta. Therefore, in Alzh eimer's disease, deposits of A beta fibrils alone may be sufficient to indu ce a chronic release of neurotoxic microglial products, explaining the prog ressive neurodegeneration associated with this disease. Our observation tha t systemic administration of selective iNOS inhibitors abolishes A beta-ind uced NO generation in vivo may have implications for therapy of Alzheimer's disease.