Amyloid precursor protein modulates the interaction of nerve growth factor with p75 receptor and potentiates its activation of trkA phosphorylation

We have recently shown that the secreted form of amyloid precursor protein (APP(s)) potentiates the neurotrophic actions of nerve growth factor (NGF). The combined presence of NGF and APP(s) in low concentrations resulted in a synergistic potentiation of NGF neuritogenic activity on PC12 cells. Therefore, the effect of APP(s) on NGF receptor-binding has been examined. In the presence of APP(s), the apparent affinity of NGF' s low affinity binding site increased by a factor of 2.5. In addition, a 2- to 2.5-fold decrease in the number of sites was observed, although APP(s) did not compete with NGF for the same binding sites. These effects of APP(s) were not caused by direct interaction with NGF itself. In addition, APP(s) synergistically potentiated the tyrosine phosphorylation of trkA due to NGF. These results suggest that an increased affinity of p75 for NGF may underlie the potentiation of neurotrophic actions of NGF by APP(s), and that increase may be caused by an indirect interaction between APP(s) and p75. (C) 1998 Elsevier Science B.V.