EXPRESSION AND FUNCTION OF THE LOW-DENSITY-LIPOPROTEIN RECEPTOR-RELATED PROTEIN (LRP) IN MAMMALIAN CENTRAL NEURONS

The low density lipoprotein receptor-related protein (LRP) is a multif unctional cell surface receptor, expressed in liver, that binds with h igh affinity and endocytoses several structurally and functionally dis tinct ligands, including apolipoprotein E-activated beta-migrating ver y low density lipoprotein, tissue-type plasminogen activator, and alph a(2)-macroglobulin. Here using in situ hybridization and quantitative RNase protection assays, we show that LRP is also expressed throughout the brain. LRP message is particularly high in the cerebellum, cortex , hippocampus, and brain stem. In addition, we demonstrate that a 39-k Da protein which copurifies with LRP and regulates the binding of othe r ligands to LRP is also expressed throughout the brain. Interestingly , expression of the 39 kDa message is similar to 100-fold of that foun d in liver, suggesting that the activity of LRP is more tightly regula ted in brain tissue than in liver. Using primary cultures of isolated postnatal cortical neurons, [S-35]methionine biosynthetic labeling and immunoprecipitation, we also demonstrate the de novo biosynthesis of LRP, the 39-kDa protein, as well as tissue-type plasminogen activator. Finally, using radioligand binding as well as fluorescent ligand bind ing and uptake studies, we show that LRP is functional in cortical neu rons. These results taken together thus demonstrate expression of func tional LRP in neuronal cells and suggest a potential role for LRP in b rain protein and lipoprotein metabolism, development, and regeneration .