Secreted amyloid precursor protein-α upregulates synaptic protein synthesis by a protein kinase G-dependent mechanism

Secreted amyloid precursor protein-α (sAPPα) is a neuroprotective and neurotrophic protein derived from the parent APP molecule. We have shown that sAPPα enhances long-term potentiation in vivo and can restore spatial memory in rats whose endogenous sAPPα production is impaired. These observations imply that the reduction of sAPPα levels seen in Alzheimer's disease, which occurs alongside increased levels of toxic amyloid-β, may be aetiologically significant. The mechanism by which sAPPα brings about changes in plasticity at synapses remains unresolved. We hypothesised that sAPPα may stimulate changes in synaptodendritic protein synthesis, an important mechanism for normal plasticity. To test this hypothesis, we investigated the effect of sAPPα on protein synthesis in synaptoneurosomes prepared from the hippocampi of adult male Sprague–Dawley rats. sAPPα (10 nM) significantly increased de novo protein synthesis as measured by the incorporation of [ 35S]-methionine into acid-insoluble proteins. This was dose-dependent and blocked completely by inhibitors of protein synthesis (cycloheximide) and of cGMP-dependent protein kinase (KT5823). Inhibitors of calcium/calmodulin-dependent protein kinases (KN62) and mitogen-activated protein kinase (PD98059) partially blocked the response. Further, the sAPPα-induced increase in protein synthesis was significantly attenuated when measured in synapses isolated from aged rats. These observations imply de novo protein synthesis at synapses may contribute to the long-lasting modulatory effects of sAPPα on synaptic plasticity.