Neurotrophin binding to the p75 neurotrophin receptor is necessary but notsufficient to mediate NGF-effects on APP secretion in PC-12 cells

In the present study the pheochromocytoma cell line (PC-12) was used as a m odel system to determine the role of the two neurotrophin receptors in the regulation of amyloid precursor protein (APP) secretion by nerve growth fac tor (NGF). To stimulate TrkA and/or p75(NTR) Signaling in PC-12 cells, we u sed NGF, brain-derived neurotrophic factor (BDNF), and NGF in the presence of an excess of BDNF or the monoclonal antibody 192IgG, to block p75(NTR) b inding to NGF. Our results demonstrate that NGF stimulates APP secretion in a dose dependent fashion with maximum effects at 10 ng/ml, known to satura te high-affinity NGF binding sites. Treatment of PC-12 cells with varying c oncentrations of BDNF, 1-1,000 ng/ml, did not alter APP secretion, suggesti ng that binding to p75(NTR) alone is not sufficient to affect APP secretion . When blocking NGF binding to p75(NTR) With BDNF or 192IgG, on the other h and, NGF effects on APP secretion were abolished. These findings suggest th at in cells expressing p75(NTR) and TrkA receptors, binding of NGF to the p 75(NTR) is required to mediate NGF effects on APP secretion. Our data are a lso consistent with a proposed function of the p75(NTR) in receptor recruit ment and "presentation" of NGF to receptors.