NERVE GROWTH-FACTOR INDUCES RAPID INCREASES IN FUNCTIONAL CELL-SURFACE LOW-DENSITY-LIPOPROTEIN RECEPTOR-RELATED PROTEIN

The low density lipoprotein receptor-related protein (LRP) is a large endocytic receptor that binds multiple ligands and is highly expressed in neurons. Several LRP ligands, including apolipoprotein E/lipoprote ins and amyloid precursor protein, have been shown to participate eith er in Alzheimer's disease pathogenesis or pathology. However, factors that regulate LRP expression in neurons are unknown. In the current st udy, we analyzed the effects of nerve growth factor (NGF) treatment on LRP expression, distribution, and function within neurons in two neur onal cell lines. Our results show that NGF induces a rapid increase of cell surface LRP expression in a central nervous system-derived neuro nal cell line, GT1-1 Trk, which was seen within 10 min and reached a m aximum at about 1 h of NGF treatment. This increase of cell surface LR P expression is concomitant with an increase in the endocytic activity of LRP as measured via ligand uptake and degradation assays. We also found that the cytoplasmic tail of LRP is phosphorylated and that NGF rapidly increases the amount of phosphorylation. Furthermore, we detec ted a significant increase of LRP expression at the messenger RNA leve l following 24 h of NGF treatment. Both rapid and long term induction of LRP expression were also detected in peripheral nervous system-deri ved PC12 cells following NGF treatment. Taken together, our results de monstrate that NGF regulates LRP expression in neuronal cells.