P4‐069: Secreted Amyloid Precursor Protein‐Alpha Enhances Long‐Term Potentiation Via Protein Synthesis‐ and Protein Trafficking‐Dependent Mechanisms

Secreted amyloid precursor protein-alpha (sAPPα), a peptide derived from amyloid precursor protein, has been shown to enhance synaptic plasticity both in rats and in a mouse model of Alzheimer’s disease. However, the mechanisms of its wide-ranging effects are not well understood. Here we investigated whether prior exposure to sAPPα “primed” long-term potentiation (LTP) and whether protein synthesis and protein trafficking is required for sAPPα-mediated enhancement of synaptic plasticity. Acute hippocampal slices were prepared from adult male Sprague-Dawley rats and allowed to recover for 2 h. Baseline field excitatory postsynaptic potentials (EPSPs) were evoked in area CA1 by electrical stimulation of the Schaffer collateral/commissural pathway, and recorded in stratum radiatum. Short-term potentiation (STP) or long-term depression (LTD) were induced by mild theta-burst stimulation (TBS) or 1 hz stimulation, respectively. Application of mild TBS (5 trains of 5 pulses at 100 Hz, applied at 200 ms intervals) induced STP but not LTP (EPSPs: 8.3 ± 4.2% above baseline, n=10, 1 h post-TBS). By contrast, bath application of sAPPα (1 nM) 30 min prior to and during the mild TBS resulted in significant LTP (45.4 ± 5.5%, n=8; p<0.001) compared to control slices. When we washed the sAPPα out of the bath for 30 min prior to TBS delivery, LTP was still facilitated (38.8 ± 4.8% above baseline 120 min post-TBS; n=6), and significantly different from control slices (8.4 ± 3.0%, n=9; p=0.0001). This sAPPα-mediated metaplasticity was blocked by inhibition of protein synthesis with cycloheximide (60 μM) during the sAPPα administration. Inhibition of protein trafficking with brefeldin A (BFA, 35 μM) caused only a modest reduction in sAPPα-mediated LTP but a significant decrease in post-tetanic potentiation in the five minutes post-TBS. By contrast, sAPPα had no effect on LTD induced either by 900 pulses delivered at 1 Hz or 1200 pulses at 1 Hz to the Schaffer collateral pathway. These results suggest that sAPPα primes LTP by promoting protein trafficking during the early stages of LTP and promotes the maintenance of LTP by enhancing protein synthesis. Supported by the New Zealand Health Research Council.