Secreted forms of β-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 β-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 β-amyloid precursor protein antibodies showed that immunoreactivity was concentrated in axons and, particularly, in their growth cones. Because β-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.