Upon acute activation, microglia, the immuneffector cells of the brain parenchyma, express the amyloid precursor protein (APP) that is otherwise prominent in pathological structures related to Alzheimer's disease. In this disease complex amyloid-bearing neuritic plaques contain beta A4-amyloid protein, the APP, and numerous inflammatory proteins. The accompanying activation of microglia has mostly been viewed as a secondary reaction to amyloid deposits. Activation of microglia was performed in a graded fashion. Transection of peripheral nerves such as the facial or sciatic nerve causes a microglial reaction within hours in the nucleus of origin or in projection areas of the CNS. A predominantly glial up-regulation of APP mRNA and protein could be detected as early as 6 h post lesion not only at the site of affected neuronal cell bodies but also in corresponding projection areas. Its time course suggests rapid transneuronal signalling to glial cells in the projection area. Light and electron microscopy demonstrate that microglia, which are cells of mononuclear phagocyte lineage and comprise up to 20% of all glial cells, are the dominant source for non-neuronal APP expression. Ultrastructurally, brain perivascular cells within the basal lamina constitutively express APP and thus are a possible source of vascular amyloid. Additionally, microglia express leukocyte-derived (L)-APP mRNA and protein that have recently been described in mononuclear cells of the immune system. Increased L-APP expression may serve as a potential marker for glial/microglial activation. Such immune-mediated amyloidogenesis initiated by microglia might have implications for the treatment of neurodegenerative diseases.