CELL-SURFACE BETA-AMYLOID PRECURSOR PROTEIN STIMULATES NEURITE OUTGROWTH OF HIPPOCAMPAL-NEURONS IN AN ISOFORM-DEPENDENT MANNER

beta-Amyloid precursor protein (beta APP) is an integral membrane poly peptide expressed in many neural and non-neural cells, beta APP occurs in part at the cell surface and undergoes proteolytic processing to r elease the large soluble ectodomain (APP(s)) and the amyloid beta-pept ide (A beta), both of which have apparent trophic activity in vitro. D espite intense interest in beta APP expression and metabolism, there i s limited knowledge about the function mediated by beta APP inserted a t the cell-surface. We established a coculture system in which beta AP P-transfected CHO cells serve as a substrate for the growth of primary rat hippocampal neurons. Compared to nontransfected CHO cells, the in creased surface beta APP of the transfectants stimulated short-term ne uronal adhesion and longer-term neurite outgrowth, whereas the increas ed amount of secreted APP(s) and A beta in conditioned medium produced no such effects when neurons were grown either on untransfected CHO c ells or on a polylysine substrate. Moreover, a peptide which has been shown to block the trophic effects of secreted APP(s) (Ninomiya et al. , 1993) failed to interrupt the neurite promoting activity mediated by the surface-expressed beta APP. Surface-expressed beta APP(751) or be ta APP(770) isoforms mediated more neurite outgrowth than did the beta APP(695) isoform. Antibody blocking and regional deletion experiments indicated that the mid-region of the beta APP ectodomain (residues 36 1-648) is involved in promoting neurite outgrowth. We conclude that su rface-expressed cellular beta APP has a neurite-promoting function whi ch is distinct from the trophic function of the secreted beta APP deri vatives and may have special significance during brain development.