Secreted amyloid precursor protein alpha selectively suppresses N-methyl-D-aspartate currents in hippocampal neurons: involvement of cyclic GMP

The secreted form of beta-amyloid precursor protein (sAPP alpha) is released from neurons in an activity-dependent manner; data suggest sAPP alpha may play roles in regulating neuronal excitability, plasticity, and survival. In cultured hippocampal neurons sAPP alpha can suppress elevation of [Ca2+]i induced by glutamate and can protect neurons against excitotoxicity. We now report whole-cell patch-clamp data from studies of cultured embryonic rat hippocampal neurons which demonstrate that sAPP alpha selectively suppresses N-methyl-D-aspartate currents without affecting currents induced by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate or kainate. sAPP alpha suppressed N-methyl-D-aspartate current rapidly and reversibly at concentrations of 0.011 nM. Suppression of N-methyl-D-aspartate current by sAPP alpha is apparently mediated by cyclic guanosine monophosphate because 8-bromo-cyclic guanosine monophosphate suppressed N-methyl-D-aspartate current in a manner similar to sAPP alpha, and two different inhibitors of cyclic guanosine monophosphate-dependent protein kinase prevented sAPP alpha-induced suppression of N-methyl-D-aspartate current. In addition, okadaic acid prevented suppression of N-methyl-D-aspartate-induced current suggesting the involvement of a protein phosphatase in modulation of N-methyl-D-aspartate current by sAPP alpha. These data identify a mechanism whereby sAPP alpha can modulate cellular responses to glutamate, and suggest important roles for sAPP alpha in the various physiological and pathophysiological processes in which N-methyl-D-aspartate receptors participate.