Glutamate Receptor Trafficking and Protein Synthesis Mediate the Facilitation of LTP by Secreted Amyloid Precursor Protein-Alpha

Secreted amyloid precursor protein-alpha (sAPP alpha) has growth factor-like properties and can modulate long-term potentiation (LTP) and memory. Here, we demonstrate that exposure to sAPP alpha converts short-lasting LTP into protein-synthesis-dependent late LTP in hippocampal slices from male rats. sAPP beta had no discernable effect. We hypothesized that sAPP alpha facilitated LTP via regulated glutamate receptor trafficking and de novo protein synthesis. We found using a linear mixed model that sAPP alpha stimulated trafficking of GluA2-lacking AMPARs, as well as NMDARs to the extrasynaptic cell surface, in a calcium/calmodulin-dependent kinase II and protein kinase G-dependent manner. Both cell surface receptor accumulation and LTP facilitation were present even after sAPP alpha washout and inhibition of receptor trafficking or protein synthesis prevented all these effects. Direct visualization of newly synthesized proteins (FUNCAT-PLA) confirmed the ability of sAPP alpha to stimulate de novo protein synthesis and revealed GluA1 as one of the upregulated proteins. Therefore, sAPP alpha generates a coordinated synthesis and trafficking of glutamate receptors to the cell surface that facilitate LTP.