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

The secreted form of β-amyloid precursor protein (sAPPα) is released from neurons in an activity-dependent manner; data suggest sAPPα may play roles in regulating neuronal excitability, plasticity, and survival. In cultured hippocampal neurons sAPPα 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 sAPPα selectively suppresses N- methyl-D-aspartate currents without affecting currents induced by α-amino- 3-hydroxy-5-methylisoxazole-4-propionate or kainate. sAPPα suppressed N- methyl-D-aspartate current rapidly and reversibly at concentrations of 0.01- 1 nM. Suppression of N-methyl-D-aspartate current by sAPPα is apparently mediated by cyclic guanosine monophosphate because 8-bromo-cyclic guanosine monophosphate suppressed N-methyl-D-aspartate current in a manner similar to sAPPα, and two different inhibitors of cyclic guanosine monophosphate- dependent protein kinase prevented sAPPα-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 sAPPα. These data identify a mechanism whereby sAPPα can modulate cellular responses to glutamate, and suggest important roles for sAPPα in the various physiological and pathophysiological processes in which N-methyl-D-aspartate receptors participate.