A New Function for the LDL Receptor: Transcytosis of LDL across the Blood–Brain Barrier

Abstract

Lipoprotein transport across the blood–brain barrier (BBB) is of critical importance for the delivery of essential lipids to the brain cells. The occurrence of a low density lipoprotein (LDL) receptor on the BBB has recently been demonstrated. To examine further the function of this receptor, we have shown using an in vitro model of the BBB, that in contrast to acetylated LDL, which does not cross the BBB, LDL is specifically transcytosed across the monolayer. The C7 monoclonal antibody, known to interact with the LDL receptor-binding domain, totally blocked the transcytosis of LDL, suggesting that the transcytosis is mediated by the receptor. Furthermore, we have shown that cholesterol-depleted astrocytes upregulate the expression of the LDL receptor at the BBB. Under these conditions, we observed that the LDL transcytosis parallels the increase in the LDL receptor, indicating once more that the LDL is transcytosed by a receptor-mediated mechanism. The nondegradation 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 to a transcytotic receptor cannot be explained by a modification of the internalization signals of the cytoplasmic domain of the receptor, since we have shown that LDL receptor messengers in growing brain capillary 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 polymeric immunoglobulin receptor. Preliminary studies suggest that caveolae are likely to be involved in the potential transport of LDL from the blood to the brain.

Functional Protein Delivery into Neurons Using Polymeric Nanoparticles

“…Prior studies suggest that these NPs can be transcytosed across the brain capillary endothelium via an LDL receptor-dependent pathway, perhaps by forming a complex with LDL in the bloodstream (12,14,41). These studies did not evaluate uptake of PBCA NPs into neurons and glia, however.…”

“…Lipoprotein transport across the BBB is crucial for the delivery of essential lipids to brain cells, and direct evidence has been provided for the existence of a LDL receptor in vivo on the BBB (13). LDLs have further been shown to undergo transcytosis across the brain capillary endothelium without apparent degradation by endothelial cells, and they may therefore gain entry into other tissues following pas-sage across the BBB (14). However, whether NPs actually gain entry into neuronal cells has not been demonstrated.…”

Fatty Acid Derivatives of Clozapine Prolonged Antidopaminergic Activity of Docosahexaenoylclozapine in the Rat

“…Saturated fatty acids, especially those with relatively short carbon-chains, enter by a probenecid-sensitive, low-affinity, high-capacity transport process that may involve protein receptor or carrier molecules, whereas entry of unsaturated fatty acids occurs through a less well understood process that is not inhibited by probenecid (Spector 1988;Avellini et al 1994). Further complication is introduced by the uncertain role of circulating albumin and proteolipids as avid carriers of fatty acids that reach the brain, possibly through the mediation of low-density proteo- lipid receptor proteins at the blood-brain barrier (Spector 1988;Avellini et al 1994;Dehouck et al 1997). The tendency for fatty acids to attach to proteins may also contribute to the prolonged actions of DHA-clozapine.…”

Increased locomotor activity in mice lacking the low-density lipoprotein receptor

“…Low but detectable levels of LDLR RNA are found in brain [15]. As judged by in situ hybridization, LDLR expression is widely distributed in brain [30] and likely found in neurons, astrocytes, and endothelial cells [9,10,15,22,25,30]. However, LDLR null mutant mice (LDLR-/-) show no obvious anatomic defects in brain and thus LDLR has been considered to be of lesser importance in brain development and function than other family members such as LRP, ApoER2, or VLDLR [13].…”