Localization of mRNA for low density lipoprotein receptor and a cholesterol synthetic enzyme in rabbit nervous system by in situ hybridization.

Abstract

The low density lipoprotein receptor and one of its ligands, apoprotein E, are known to be synthesized in the central nervous system. In the current study, we used in situ hybridization to localize the receptor mRNA in selected neurons and glia throughout the nervous system of 9-day-old rabbits. Particularly high levels were found in sensory ganglia, sensory nuclei, and motor-related nuclei. The same regions contained high levels of mRNA for 3-hydroxy-3-methylglutaryl-coenzyme A synthase, a regulated enzyme in cholesterol biosynthesis. The distribution of low density lipoprotein receptor mRNA was similar in mature and immature rabbits. The data suggest that certain cells in the nervous system have high requirements for cholesterol, which they satisfy through cholesterol synthesis and through receptor-mediated uptake of cholesterol-carrying lipoproteins. The latter originate in astrocytes which synthesize and secrete apoprotein E. These data suggest that the nervous system of mammals contains an active system for continuous redistribution and recycling of cholesterol that is physically distinct from the lipoprotein transport system in plasma.The low density lipoprotein (LDL) receptor binds cholesterol-carrying plasma lipoproteins that contain apoprotein (apo) B-100 or apoE. Binding leads to cell uptake by receptormediated endocytosis, thereby supplying cholesterol to cells (1). The production of LDL receptors is driven by a cell's cholesterol requirement. Cells that require large amounts of cholesterol, such as those in the liver and adrenal gland and those that grow in tissue culture, produce relatively large numbers of LDL receptors. Cells with low requirements, such as resting lymphocytes, produce few receptors. When the LDL receptor is genetically defective, as in patients with familial hypercholesterolemia or in Watanabe heritablehyperlipidemic (WHHL) rabbits, LDL is not taken up by cells normally, and plasma LDL levels rise (2).One of the ligands for the LDL receptor, apoB-100, is secreted almost exclusively by the liver (3). The other ligand, apoE, is secreted by hepatic and extrahepatic cells. One nonhepatic cell type shown to secrete apoE is the peritoneal macrophage (4). When loaded with excess cholesterol, macrophages secrete cholesterol-containing lipoproteins that contain apoE, which targets the lipoproteins to LDL receptors. ApoE-containing lipoproteins are also secreted by macrophages that enter damaged peripheral nerves and become engorged with cholesterol derived from degraded myelin (5,6). When the nerve regenerates, the neurons and Schwann cells produce LDL receptors and this allows them to use the lipoprotein-bound cholesterol secreted from the macrophages. Thus, apoE and the LDL receptor play a role in the healing of peripheral nerves.A role for apoE in the central nervous system (CNS) was demonstrated by Boyles et al. (5), who showed by immunocytochemistry that astrocytes produce apoE. This finding stimulated a search for LDL receptors in the brain. Hofmann et al. (7), using RNA blot...

Localization of Niemann–Pick C1 protein in astrocytes: Implications for neuronal degeneration in Niemann– Pick type C disease

“…This suggests that neuronal processes may have a requirement for cholesterol delivery from exogenous sources such as astrocytes. In this respect, it is of interest that several apolipoproteins that mediate cholesterol transfer functions in plasma, as well as lipoprotein receptors such as the LDL receptor (LDLR) and LDLR-related protein (LRP), are also expressed in neural tissues (28)(29)(30). Functional disruption of the LDLR and apoE genes in mice, however, do not cause gross neurological abnormalities (31,32), and neither apoE nor apoA1 within lipoproteins are essential for axonal growth in vitro (33).…”

Neurotoxicity of the 22 kDa Thrombin-Cleavage Fragment of Apolipoprotein E and Related Synthetic Peptides Is Receptor-Mediated

“…The LDL receptor, for example, is localized primarily to astrocytes and the neuropil (Pitas et al, 1987;Swanson et al, 1988;Rebeck et al, 1993) but does not appear to be expressed by neurons. LRP, which was originally cloned from human cells (Herz et al, 1988), but includes highly homologous receptors in the chicken and Caenorhabditis elegans (Yochem et al, 1993), is widely expressed by neurons (Moestrup et al, 1992;Wolf et al, 1992;Rebeck et al, 1993;Bu et al, 1994;Ishiguro et al, 1995).…”

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].…”