The Biological Function of Amyloid β/A4 Protein Precursor

Amyloid β/A4 protein precursor (APP) is secreted into medium by most cultured cells and can function as an autocrine factor. To study the biological function of secreted forms of APP (sAPP) on neurons, we used a clonal CNS neuronal line B103 which synthesizes no detectable levels of APP. When B103 cells were plated at a low density in a defined serum-free medium, neurite outgrowth was promoted by the conditioned medium of APP-695 over-producing cells and by the bacteria-produced sAPP-695 (named KB75). A series of peptides having sequences between Ala-319 and Met-335 of APP-695 also stimulated neurite outgrowth of B103 cells. The sequence of five amino acids, RERMS (APP 328–332) within this stretch of sequence, was the shortest active peptide. Binding assay using 125l-labeled APP 17-mer peptide corresponding to Ala-319 to Met-335 of APP-695 as a ligand demonstrated specific and saturable cell-surface binding sites which are extractable with detergent. These data indicate that sAPP induces neurite extension through a cell surface binding and that the RERMS domain represents the active site responsible for this function. The RERMS-containing APP peptide also exhibited neuronal survival activity on rat primary cortical neuronal culture. In addition, the infusion of the trophic APP peptide into rat brain ventricles increased the synaptic density in the frontoparietal cortex and enhanced the memory retention. These results firmly establish the neurotrophic properties of sAPP and raise the possibility that small APP peptides or non-peptidic compounds mimicking their activity may be used therapeutically for the improvement of memory performance.