THE LOW-DENSITY-LIPOPROTEIN RECEPTOR GENE FAMILY - DIFFERENTIAL EXPRESSION OF 2 ALPHA(2)-MACROGLOBULIN RECEPTORS IN THE BRAIN

LR7/8B is a member of the low density lipoprotein receptor gene family that is specifically synthesized in the brain. Here we have functiona lly expressed in 293 cells the splice variant harboring eight ligand b inding repeats (LR8B), As assessed by confocal microscopy, the express ed receptor is localized to the plasma membrane. Importantly, in cell binding experiments, we demonstrate that this protein is a receptor fo r activated cy,macroglobulin, Because to date low density lipoprotein receptor-related protein (LRP) has been shown to be the only alpha(2)- macroglobulin receptor in brain, we became interested in the expressio n pattern of both proteins at the cellular level in the brain. LR7/8B is expressed in large neurons and Purkinje cells of the cerebellum and in cells constituting brain barrier systems such as the epithelial ce lls of the choroid plexus, the arachnoidea, and the endothelium of pen etrating blood vessels. Anti-LR7/8B antibody stains the plasma membran e, dendrites, and vesicular structures close to the cell membrane of n eurons, especially of Purkinje cells. In contrast, LRP is present in p atchy regions around large neurons and most prominently in the glomeru li of the stratum granulare of the cerebellum. This suggests that, con trary to LR7/8B, LRP is expressed in synaptic regions of the neurons; furthermore, there is a striking difference in the expression patterns of LR7/8B and LRP in the choroid plexus. Whereas LRP shows base-later al and apical localization in the epithelial cells, LR7/8B is restrict ed to the apical cell aspect facing the cerebrospinal fluid. Finally, these studies were extended to cultured primary rat neurons, where dou ble immunofluorescence labeling with anti-LR7/8B and anti-microtubuli- associated protein 2 (MAPS) confirmed the somatodendritic expression o f the receptor. Based upon these data, we propose that LR7/8B is invol ved in the clearance of alpha(2)-macroglobulin proteinase complexes an d/or of other substrates bound to alpha(2)-macroglobulin from the cere brospinal fluid and from the surface of neurons.