SECRETED FORMS OF BETA-AMYLOID PRECURSOR PROTEIN MODULATE DENDRITE OUTGROWTH AND CALCIUM RESPONSES TO GLUTAMATE IN CULTURED EMBRYONIC HIPPOCAMPAL-NEURONS

In addition to being the major excitatory neurotransmitter in the mammalian brain, glutamate is believed to play a key role in the regulation of neurite outgrowth and synaptogenesis during development. In cultured embryonic hippocampal pyramidal neurons, glutamate inhibits dendrite outgrowth by a mechanism involving elevation of intracellular-free calcium levels ([Ca2+](i)). In the present study, secreted forms of the beta-amyloid precursor protein (APP(s)s) counteracted the inhibitory effect of glutamate on dendrite outgrowth in cultured embryonic hippocampal neurons. The prolonged elevation of [Ca2+](i) normally induced by glutamate was significantly attenuated in neurons that had been pretreated with 2-10 nM of APP(s)695 or APP(s)751. Immunocytochemistry with beta-amyloid precursor protein antibodies showed that immunoreactivity was concentrated in axons and, particularly, in their growth cones. Because beta-amyloid precursor proteins are axonally transported, and APP(s)s can be released from axon terminals/growth cones in response to electrical activity, the present findings suggest that APP(s)s may play a role in developmental and synaptic plasticity by modulating dendritic responses to glutamate. (C) 1994 John Wiley and Sons, Inc.