Implication of apoE isoforms in cholesterol metabolism by primary rat hippocampal neurons and astrocytes

Rapp, Alfred; Gmeiner, Bernhard; Hüttinger, Manfred

doi:10.1016/j.biochi.2005.10.007

Cited by 107 publications

(71 citation statements)

References 43 publications

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“…Although both LDLR and LRP1 play roles in brain apoE/lipoprotein metabolism, there are important differences between them. First, whereas LRP1 is highly expressed in neurons and to a lesser degree in glia, LDLR is more prominently expressed in glia than neurons (Rebeck et al 1993;Rapp et al 2006). Second, deletion of the Lrp1 gene in mouse forebrain neurons reduces brain cholesterol levels (Liu et al 2007), whereas cholesterol levels in Ldlr knockout mice are unchanged (Fryer et al 2005a).…”

Section: Lrp1 and Ldlr In Cellular And Brain Ab Metabolismmentioning

confidence: 99%

“…There is some evidence that apoE isoforms may differ in their function in regard to cholesterol transport and efflux (Michikawa et al 2000;Gong et al 2002;Rapp et al 2006), although not all studies show this (Hirsch-Reinshagen et al 2004). Thus the roles of apoE isoforms in brain cholesterol metabolism require further investigation.…”

Section: Lrp1 and Ldlr In Cellular And Brain Ab Metabolismmentioning

confidence: 99%

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Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

Holtzman

Herz²,

2012

Cold Spring Harbor Perspectives in Medicine

681

602

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Section: Lrp1 and Ldlr In Cellular And Brain Ab Metabolismmentioning

confidence: 99%

Section: Lrp1 and Ldlr In Cellular And Brain Ab Metabolismmentioning

confidence: 99%

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

Holtzman

Herz²,

2012

Cold Spring Harbor Perspectives in Medicine

681

602

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“…In the early 1980s, it was observed that liver sinusoidal endothelial cells endocytose circulating HA (15)(16)(17)(18)(19). We know now that HA⅐HARE complexes are endocytosed via the clathrin-coated pit pathway (20,21), and their formation is cation-independent (22), specific, and of high affinity (23,24).…”

mentioning

confidence: 99%

Expression, Processing, and Glycosaminoglycan Binding Activity of the Recombinant Human 315-kDa Hyaluronic Acid Receptor for Endocytosis (HARE)

Harris

Kyosseva

Weigel

et al. 2007

Journal of Biological Chemistry

120

156

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The hyaluronic acid (HA) receptor for endocytosis (HARE; also designated stabilin-2 and FEEL-2) mediates systemic clearance of glycosaminoglycans from the circulatory and lymphatic systems via coated pit-mediated uptake. HARE is primarily found as two isoforms ( The glycosaminoglycan (GAG)2 hyaluronic acid (HA) is a protein-free polymer of disaccharide units containing glucuronic acid and N-acetylglucosamine (1, 2). HA is involved in many physiological processes (3), such as wound healing, development, and metastasis of some cancers (4 -8). The typical molecular mass of the polysaccharide ranges from just a few thousand Da (tens of sugars) that are thought to be important in cellular signaling (6) to several million Da (tens of thousands of sugars). These larger forms of HA are present throughout the body and are particularly concentrated within the bursa of major joints, such as the knee, where they help to provide shock absorbance in cartilage or lubrication in synovial fluid (9, 10), and the eye, where HA maintains structural integrity of the vitreous humor (11). The adult human body contains ϳ15 g of HA, of which about 5 g are turned over daily (12). Partially degraded HA perfuses from extracellular matrices (ECMs) and enters the lymphatic and vascular circulation systems, where it is catabolized to shorter fragments. This active maintenance of HA turnover must be efficient in order to maintain homeostatic conditions for total body HA.All of the other GAGs, including the chondroitin sulfates (CSs), heparan sulfate (HS), and keratan sulfate, are linked to core proteins (as proteoglycans) that help to form ECMs, such as the basement membranes of tissues, or structural components of organs, such as the vitreous humor. There are over 30 known core proteins that are essential for a diverse array of functions, such as neural development, growth factor signaling, and pathogen recognition (13). These core proteins are found as prevalent components of tissue ECMs or as specialized components needed for the development of microenvironments that interface a specialized tissue cell type with the ECM. Both the proteoglycans and their attached GAG chains may combinatorially interact with ligands and contribute to modulation of the functional aspects of a particular microenvironment (e.g. CS interacting with apolipoprotein E for uptake of ␤-very low density lipoprotein in hippocampal neurons) (14). Although numerous studies have focused on how the inhibition of some CS proteoglycans enhances neural development, especially in injured spinal cord models, there is very little information on how CS and HS are catabolized. The current model is that extracellular chondroitinases, heparinases, and proteases initially break down these GAGs and proteoglycans, and their final digestion can then take place intracellularly at the local tissue * This research was supported by NIGMS, National Institutes of Health, Grant GM69961. The costs of publication of this article were defrayed in part by the payment of page charges. This article ...

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“…Cholesterol uptake by cultured neuronal cells is lower when the lipid is bound to APOE4 compared with APOE2 and APOE3 ( 146 ). APOE4 is less effi cient than the other forms to stimulate cholesterol effl ux from astrocytes and neuronal cells.…”

Section: Role Of Apoe and Its Different Isoforms In Ad And Other Neurmentioning

confidence: 96%

Genetic connections between neurological disorders and cholesterol metabolism

Björkhem

Leoni²,

Meaney³

2010

Journal of Lipid Research

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and store such a large amount of cholesterol indicates that there is a close link between the evolution of the nervous system and a specifi c role for cholesterol. Within the brain, some 70% of cholesterol is present in myelin, where it fulfi lls a critical insulating role. It is likely that the requirement for effi cient signaling despite a small transverse diameter of axons was a key selective pressure driving the accretion of cholesterol in the mammalian brain ( 1, 2 ). The requirement for large amounts of cholesterol is further underscored by the long half-life of brain cholesterol; overall brain cholesterol turns over some 250-300 times slower than that in the circulation ( 3 ).At a cellular level, the myelin sheath consists of sections of plasma membrane repeatedly wrapped around an axon, with the extrusion of virtually all of the cytoplasm. Myelin is formed by 2 very specialized cells: the oligodendrocyte in the central nervous system (CNS) and the Schwann cell in the peripheral nervous system (PNS). Because an individual axon may be ensheathed by myelin from several oligodendrocytes, periodic gaps are present in the sheath. These are called the "nodes of Ranvier" and are the site of propagation of the action potential. Myelin can thus be regarded as a discontinuous insulation that enables the saltatory conduction of the action potential ( 1, 2 ). In addition Abstract Cholesterol is an essential component of both the peripheral and central nervous systems of mammals. Over the last decade, evidence has accumulated that disturbances in cholesterol metabolism are associated with the development of various neurological conditions. In addition to genetically defi ned defects in cholesterol synthesis, which will be covered in another review in this Thematic Series, defects in cholesterol metabolism (cerebrotendinous xanthomatosis) and intracellular transport (Niemann Pick Syndrome) lead to neurological disease. A subform of hereditary spastic paresis (type SPG5) and Huntington's disease are neurological diseases with mutations in genes that are of importance for cholesterol metabolism. Neurodegeneration is generally associated with disturbances in cholesterol metabolism, and presence of the E4 isoform of the cholesterol transporter apolipoprotein E as well as hypercholesterolemia are important risk factors for development of Alzheimer's disease. In the present review, we discuss the links between genetic disturbances in cholesterol metabolism and the above neurological disorders. -Björkhem, I., V. Leoni, and S. Meaney. The mammalian nervous system contains a disproportionate amount of cholesterol. In the brain, the cholesterol content is about 10-fold greater than in any other organ ( 1 ). The development of the capacity to synthesize

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Implication of apoE isoforms in cholesterol metabolism by primary rat hippocampal neurons and astrocytes

Cited by 107 publications

References 43 publications

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

Expression, Processing, and Glycosaminoglycan Binding Activity of the Recombinant Human 315-kDa Hyaluronic Acid Receptor for Endocytosis (HARE)

Genetic connections between neurological disorders and cholesterol metabolism

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