EARLY AND RAPID DE-NOVO SYNTHESIS OF ALZHEIMER BETA-A4-AMYLOID PRECURSOR PROTEIN (APP) IN ACTIVATED MICROGLIA

Upon acute activation, microglia, the immuneffector cells of the brain parenchyma, express the amyloid precursor protein (APP) that is other wise prominent in pathological structures related to Alzheimer's disea se. In this disease complex amyloid-bearing neuritic plaques contain b eta A4-amyloid protein, the APP, and numerous inflammatory proteins. T he accompanying activation of microglia has mostly been viewed as a se condary reaction to amyloid deposits. Activation of microglia was perf ormed in a graded fashion. Transection of peripheral nerves such as th e facial or sciatic nerve causes a microglial reaction within hours in the nucleus of origin or in projection areas af the CNS. A predominan tly glial up-regulation of APP mRNA and protein could be detected as e arly as 6 h post lesion not only at the site of affected neuronal cell bodies but also in corresponding projection areas. Its time course su ggests 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 expressi on. Ultrastructurally, brain perivascular cells within the basal lamin a constitutively express APP and thus are a possible source of vascula r amyloid. Additionally, microglia express leukocyte-derived (L)-APP m RNA and protein that have recently been described in mononuclear cells of the immune system. Increased L-APP expression may serve as a poten tial marker for glial/microglial activation. Such immune-mediated amyl oidogenesis initiated by microglia might have implications for the tre atment of neurodegenerative diseases. (C) 1993 Wiley-Liss, Inc.