A C-terminal peptide from secreted amyloid precursor protein-α enhances long-term potentiation in rats and a transgenic mouse model of Alzheimer's disease

Processing of the amyloid precursor protein by alternative secretases results in ectodomain shedding of either secreted amyloid precursor protein-alpha (sAPP alpha) or its counterpart secreted amyloid precursor protein-beta (sAPP beta). Although sAPPa contains only 16 additional amino acids at its C-terminus compared to sAPP beta, it displays significantly greater potency in neuroprotection, neurotrophism and enhancement of long-term potentiation (LTP). In the current study, this 16 amino acid peptide sequence (CT alpha 16) was characterised for its ability to replicate the synaptic plasticity-enhancing properties of sAPPa. An N-acetylated version of CT alpha 16 produced concentration-dependent increases in the induction and persistence of LTP at Schaffer collateral/commissural synapses in area CA1 of young adult rat hippocampal slices. A scrambled peptide had no effect. CT alpha 16 significantly enhanced de novo protein synthesis, and correspondingly its enhancement of LTP was blocked by the protein synthesis inhibitor cycloheximide, as well as by the alpha 7-nicotinic receptor blocker alpha-bungarotoxin. The impaired LTP of 14-16 month old APPswe/PS1dE9 transgenic mice, a mouse model of Alzheimer's disease, was completely restored to the wild-type level by CT alpha 16. These results indicate that the CT alpha 16 peptide fragment of sAPPa mimics the larger protein's functionality with respect to LTP, stimulation of protein synthesis and activation of alpha 7-nAChRs, and thus like sAPP alpha may have potential as a therapeutic agent against the plasticity and cognitive deficits observed in AD and other neurological disorders.