A NEW FUNCTION FOR THE LDL RECEPTOR - TRANSCYTOSIS OF LDL ACROSS THE BLOOD-BRAIN-BARRIER

Lipoprotein transport across the blood-brain barrier (BBB) is of criti cal importance for the delivery of essential lipids to the brain cells . The occurrence of a low density lipoprotein (LDL) receptor on the BB B has recently been demonstrated. To examine further the function of t his receptor, we have shown using an in vitro model of the BBB, that i n contrast to acetylated LDL, which does not cross the BBB, LDL is spe cifically transcytosed across the monolayer. The C7 monoclonal antibod y, known to interact with the LDL receptor-binding domain, totally blo cked the transcytosis of LDL, suggesting that the transcytosis is medi ated by the receptor. Furthermore, we have shown that cholesterol-depl eted astrocytes upregulate the expression of the LDL receptor at the B BB. Under these conditions, we observed that the LDL transcytosis para llels the increase in the LDL receptor, indicating once more that the LDL is transcytosed by a receptor-mediated mechanism. The nondegradati on of the LDL during the transcytosis indicates that the transcytotic pathway in brain capillary endothelial cells is different from the LDL receptor classical pathway. The switch between a recycling receptor t o a transcytotic receptor cannot be explained by a modification of the internalization signals of the cytoplasmic domain of the receptor, si nce we have shown that LDL receptor messengers in growing brain capill ary ECs (recycling LDL receptor) or differentiated cells (transcytotic receptor) are 100% identical, but we cannot exclude posttranslational modifications of the cytoplasmic domain, as demonstrated for the poly meric immunoglobulin receptor. Preliminary studies suggest that caveol ae are likely to be involved in the potential transport of LDL from th e blood to the brain.