Cell-surface β-amyloid precursor protein stimulates neurite outgrowth of hippocampal neurons in an isoform-dependent manner

β-Amyloid precursor protein (βAPP) is an integral membrane polypeptide expressed in many neural and non-neural cells. βAPP occurs in part at the cell surface and undergoes proteolytic processing to release the large soluble ectodomain (APP(s) and the amyloid β-peptide (Aβ), both of which have apparent trophic activity in vitro. Despite intense interest in βAPP expression and metabolism, there is limited knowledge about the function mediated by βAPP inserted at the cell-surface. We established a coculture system in which βAPP-transfected CHO cells serve as a substrate for the growth of primary rat hippocampal neurons. Compared to nontransfected CHO cells, the increased surface βAPP of the transfectants stimulated short- term neuronal adhesion and longer-term neurite outgrowth, whereas the increased amount of secreted APP(s) and Aβ in conditioned medium produced no such effects when neurons were grown either on untransfected CHO cells 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 βAPP. Surface-expressed βAPP₇₅₁ or βAPP₇₇₀ isoforms mediated more neurite outgrowth than did the βAPP₆₉₅ isoform. Antibody blocking and regional deletion experiments indicated that the mid-region of the βAPP ectodomain (residues 361-648) is involved in promoting neurite outgrowth. We conclude that surface-expressed cellular βAPP has a neurite-promoting function which is distinct from the trophic function of the secreted βAPP derivatives and may have special significance during brain development.