We have recently shown that the amyloid beta A4 precursor protein (APP) is synthesized in neurons and undergoes fast axonal transport to synaptic sites [Koo et al., Proc. Natl. Acad. Sci. U.S.A., 87 (1990) 1561-1565]. Using immunofluorescence, laser confocal microscopy and immunoelectron microscopy with simultaneous detection of APP and synaptophysin, we now report a preferential localization of APP at synaptic sites of human and rat brain and at neuromuscular junctions. APP is further found on vesicular elements of neuronal perikarya, dendrites and axons. The synaptic localization of APP implies (1) a role of APP in physiological synaptic activity and (2) a potential and early impairment of central synapses when synaptic APP is converted to beta A4 amyloid during the pathological evolution of Alzheimer's disease and Down's syndrome.