Chronic glial activation possibly plays a role in chronic neurodegeneration in Alzheimer's disease (AD). It has been shown that amyloid peptide is capable of activating microglial cells in vitro. The aim of this study was to further characterize the structural preconditions for amyloid peptide in order to activate glial cells and to investigate whether this peptide is also able to induce glial activation in the living brain. We observed that amyloid peptide induced strong cellular activation in primary microglial cell culture as detected by the release of stable metabolites of nitric oxide (NO), when the peptide was fibrillar. For this activation, co-stimulation with interferon-gamma was a precondition. Using microdialysis of the living brain in a rat we observed pronounced NO generation when fibrillar amyloid peptide was stereotaxically injected. Non-fibrillar amyloid peptide did not induce such a glial reaction. No administration of interferon-gamma or any other co-stimulatory factor was necessary in vivo. Thus, we show that fibrillar, but not non-fibrillar amyloid peptide induced glial activation also in vivo. In the case of the living brain, the presence of deposits of fibrillar amyloid peptide could maintain a chronic microglial activation, ultimately leading to the progressive neurodegeneration associated with Alzheimer's disease.