Cholesterol metabolism and homeostasis in the brain

Abstract

Cholesterol is an essential component for neuronal physiology not only during development stage but also in the adult life. Cholesterol metabolism in brain is independent from that in peripheral tissues due to bloodbrain barrier. The content of cholesterol in brain must be accurately maintained in order to keep brain function well. Defects in brain cholesterol metabolism has been shown to be implicated in neurodegenerative diseases, such as Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), and some cognitive deficits typical of the old age. The brain contains large amount of cholesterol, but the cholesterol metabolism and its complex homeostasis regulation are currently poorly understood. This review will seek to integrate current knowledge about the brain cholesterol metabolism with molecular mechanisms.

Keywords

cholesterol metabolism / homeostasis / apoE

References

[1] Andersson M, Elmberger PG, Edlund C, Kristensson K, Dallner G (1990) Rates of cholesterol, ubiquinone, dolichol and dolichyl-P biosynthesis in rat brain slices. FEBS Lett269: 15-18

[2] Baudry M, Yao Y, Simmons D, Liu J, Bi X (2003) Postnatal development of inflammation in a murine model of Niemann-Pick type C disease: immunohistochemical observations of microglia and astroglia. Exp Neurol184: 887-903

[3] Berg JM (2002) The complex regulation of cholesterol biosynthesis takes place at several levels. Biochemistry, 5th edn. W.H. Freeman, New York

[4] Björkhem I (2006) Crossing the barrier: oxysterols as cholesterol transporters and metabolic modulators in the brain. J Intern Med260: 493-508

[5] Björkhem I, Meaney S, Fogelman AM (2004) Brain cholesterol: long secret life behind a barrier. Arterioscler Thromb Vasc Biol24: 806-815

[6] Björkhem I, Heverin M, Leoni V, Meaney S, Dicz-falusy U (2006) Oxysterols and Alzheimer’s disease. Acta Neurol Scand114: 43-49

[7] Block RC, Dorsey ER, Beck CA, Brenna JT, Shoulson I (2010) Altered cholesterol and fatty acid metabolism in Huntington disease. J Clin Lipidol4: 17-23

[8] Boyles JK, Notterpek LM, Anderson LJ (1990) Accumulation of apolipoproteins in the regenerating and remyelinating mammalian peripheral nerve. Identification of apolipoprotein D, apolipoprotein A-IV, apolipoprotein E, and apolipoprotein A-I. J Biol Chem265: 17805-17815

[9] Brown MS, Goldstein JL (1999) A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc Natl Acad Sci96: 11041-11048

[10] Bryleva EY, Rogers MA, Chang CC, Buen F, Harris BT, Rousselet E (2010) ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD. Proc Natl Acad Sci107: 3081-3086

[11] Cahoy JD (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci28: 264-278

[12] Carstea ED, Morris JA, Coleman KG, Loftus SK, Zhang D, Cummings C (1997) Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science277: 228-231

[13] Christopherson KS (2005) Thrombospondins are astrocytesecreted proteins that promote CNS synaptogenesis. Cell120: 421-433

[14] Corder EH, Saunders AM, Strittmatter WJ (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science261: 921-923

[15] Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatanpaa K, Troncoso JC, Mattson MP (2004) Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer’s disease. Proc Natl Acad Sci USA101: 2070-2075

[16] De Chaves EI, Rusinol AE, Vance DE, Campenot RB, Vance JE (1997) Role of lipoproteins in the delivery of lipids to axons during axonal regeneration. J Biol Chem272: 30766-30773

[17] Dean M, Hamon Y, Chimini G (2001) The human ATP-binding cassette (ABC) transporter superfamily. J Lipid Res42: 1007-1017

[18] DeBose-Boyd RA, Brown MS, Li WP, Nohturfft A, Goldstein JL, Espenshade PJ (1999) Transport-dependent proteolysis of SREBP: relocation of Site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi. Cell99: 703-712

[19] DeGrella RF, Simoni RD (1982) Intracellular transport of cholesterol to the plasma membrane. J Biol Chem257: 14256-14262

[20] Di Paolo G, Kim TW (2011) Linking lipids to Alzheimer’s disease: cholesterol and beyond. Nat Rev Neurosci12: 284-296

[21] Dietschy JM, Turley SD (2004) Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res45: 1375-1397

[22] Elrick MJ, Pacheco CD, Yu T, Dadgar N, Shakkottai VG, Ware C (2010) Conditional Niemann-Pick C mice demonstrate cell autonomous Purkinje cell neurodegeneration. Hum Mol Genet19: 837-847

[23] Fagan AM, Holtzman DM (2000) Astrocyte lipoproteins, effects of apoE on neuronal function, and role of apoE in amyloid-beta deposition in vivo. Microsc Res Tech50: 297-304

[24] Fagan AM, Bu G, Sun Y, Daugherty A, Holtzman DM (1996) Apolipoprotein E-containing high density lipoprotein promotes neurite outgrowth and is a ligand for the low density lipoprotein receptor-related protein. J Biol Chem271: 30121-30125

[25] Fester L, Zhou L, Bütow A (2009) Cholesterol-promoted synaptogenesis requires the conversion of cholesterol to estradiol in the hippocampus. Hippocampus19: 692-705

[26] Fox MA, Umemori H (2006) Seeking long-term relationship: axon and target communicate to organize synaptic differentiation. J Neurochem97: 1215-1231

[27] Fukumoto H, Deng A, Irizarry MC, Fitzgerald ML, Rebeck GW (2002) Induction of the cholesterol transporter ABCA1 in central nervous system cells by liver x receptor agonists increases secreted abeta levels. J Biol Chem277: 48508-48513

[28] Fünfschilling U, Saher G, Xiao L, Möbius W, Nave KA (2007) Survival of adult neurons lacking cholesterol synthesis in vivo. BMC Neurosci2: 1-8

[29] Gelissen IC, Harris M, Rye KA, Quinn C, Brown AJ, Kockx M (2006) ABCA1 and ABCG1 synergize to mediate cholesterol export to apoA-I. Arterioscler Thromb Vasc Biol26: 534-540

[30] German DC, Liang CL, Song T, Yazdani U, Xie C, Dietschy JM (2002) Neurodegeneration in the Niemann-Pick C mouse: glial involvement. Neuroscience109: 437-450

[31] Goritz C, Mauch DH, Pfrieger FW (2005) Multiple mechanisms mediate cholesterol-induced synaptogenesis in a CNS neuron. Mol Cell Neurosci29: 190-201

[32] Gosselet F, Candela P, Sevin E, Berezowski V, Cecchelli R, Fenart L (2009) Transcriptional profiles of receptors and transporters involved in brain cholesterol homeostasis at the blood-brain barrier: use of an in vitro model. Brain Res1249: 34-42

[33] Han X, Cheng H, Fryer JD, Fagan AM, Holtzman DM (2003) Novel role for apolipoprotein E in the central nervous system. Modulation of sulfatide content. J Biol Chem278: 8043-8051

[34] Heino S, Lusa S, Somerharju P, Ehnholm C, Olkkonen VM, Ikonen E (2000) Dissecting the role of the Golgi complex and lipid rafts in biosynthetic transport of cholesterol to the cell surface. Proc Natl Acad Sci97: 8375-8380

[35] Herz J (2009) Apolipoprotein E receptors in the nervous system”. Curr Opin Lipidol20: 190-196

[36] Hirsch-Reinshagen V, Zhou S, Burgess BL, Bernier L, McIsaac SA, Chan JY (2004) Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain. J Biol Chem279: 41197-41207

[37] Hirsch-Reinshagen V, Maia LF, Burgess BL (2005) The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease. J Biol Chem280: 43243-43256

[38] Hu CY, Ong WY, Patel SC (2000) Regional distribution of NPC1 protein in monkey brain. J Neurocytol29: 765-773

[39] Hutter-Paier B, Huttunen HJ, Puglielli L, Eckman CB, Kim DY, Hofmeister A (2004) The ACAT inhibitor CP-113, 818 markedly reduces amyloid pathology in a mouse model of Alzheimer’s disease. Neuron44: 227-238

[40] Ignatius MJ, Gebicke-Harter PJ, Skene JH, Schilling JW, Weisgrabber KH, Mahley RW, Shooter EM (1986) Expression of apolipoprotein E during nerve degeneration and regeneration. Proc Natl Acad Sci USA83: 1125-1129

[41] Ignatius MJ, Shooter EM, Pitas RE, Mahley RW (1987) Lipoprotein uptake by neuronal growth cones in vitro. Science236: 950-962

[42] Ikonen E (2008) Cellular cholesterol trafficking and compartmentalization. Nat Rev Mol Cell Biol9: 125-138

[43] Janowski BA, Grogan MJ, Jones SA, Wisely GB, Kliewer SA, Corey EJ, Mangelsdorf DJ (1999) Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and LXRbeta. Proc Natl Acad Sci96: 266-271

[44] Jansen PJ, Lutjohann D, Thelen KM, von Bergmann K, van Leuven F, Ramaekers FC (2000) Absence of ApoE upregulates murine brain ApoD and ABCA1 levels, but does not affect brain sterol levels, while human ApoE3 and human ApoE4 upregulate brain cholesterol precursor levels. J Alzheimers Dis18: 319-329

[45] Jeske DJ, Dietschy JM (1980) Regulation of rates of cholesterol synthesis in vivo in the liver and carcass of the rat measured using [3H] water. J. Lipid Res21: 364-376

[46] Jurevics H, Morell P (1995) Cholesterol for synthesis of myelin is made locally, not imported into brain. J Neurochem64: 895-901

[47] Jurevics HA, Kidwai FZ, Morell P (1997) Sources of cholesterol during development of the rat fetus and fetal organs. J Lipid Res38: 723-733

[48] Kaplan MR, Simoni RD (1985) Transport of cholesterol from the endoplasmic reticulum to the plasma membrane. J Cell Biol101: 446-453

[49] Karten B, Campenot RB, Vance DE, Vance JE (2006) Expression of ABCG1, but not ABCA1, correlates with cholesterol release by cerebellar astroglia. J Biol Chem281: 4049-4057

[50] Kim WS, Weickert CS, Garner B (2008) Role of ATP-binding cassette transporters in brain lipid transport and neurological disease. J Neurochem104: 1145-1166

[51] Ko M, Zou K, Minagawa H (2005) Cholesterol-mediated neurite outgrowth is differently regulated between cortical and hippocampal neurons. J Biol Chem52: 42759-42765

[52] Koch S, Donarski N, Goetze K, Kreckel M, Stuerenburg HJ, Buhmann C (2001) Characterization of four lipoprotein classes in human cerebrospinal fluid. J Lipid Res42: 1143-1151

[53] Koldamova RP, Lefterov IM, Ikonomovic MD, Skoko J, Lefterov PI, Isanski BA (2003) 22R-hydroxycholesterol and 9-cis-retinoic acid induce ATP-binding cassette transporter A1 expression and cholesterol efflux in brain cells and decrease amyloid beta secretion. J Biol Chem278: 13244-13256

[54] Korade Z, Kenworthy AK (2008) Lipid rafts, cholesterol, and the brain. Neuropharmacology55: 1265-1273

[55] Lahiri DK (2004) ApolipoproteinEasatargetfordevelopingnew therapeutics for Alzheimer’s disease based on studies from protein, the gene. J Mol Neurosci23: 225-233

[56] Lange Y, Ye J, Strebel F (1995) Movement of 25-hydroxycholesterol from the plasma membrane to the rough endoplasmic reticulum in cul- tured hepatoma cells. J Lipid Res36: 1092-1097

[57] Levi O, Lutjohann D, Devir A, von Bergmann K, Hartmann T, Michaelson DM (2005) Regulation of hippocampal cholesterol metabolism by apoE and environmental stimulation. J Neurochem95: 987-997

[58] Li Y, Lu W, Marzolo MP, Bu G (2001) Differential functions of members of the low density lipoprotein receptor family suggested by their distinct endocytosis rates. J Biol Chem276: 18000-18006

[59] Liang Y, Lin S, Beyer TP, Zhang Y, Wu X, Bales KR, DeMattos RB, May PC, Li SD, Jiang XC, Eacho PI, Cao G, Paul SM (2004) A liver X receptor and retinoid X receptor heterodimer mediates apolipoprotein E expression secretion and cholesterol homeostasis in astrocyte. J NeuroChem88: 623-634

[60] Linetti A, Fratangeli A, Taverna E, Valnegri P, Francolini M, Cappello V (2010) Cholesterol reduction impairs exocytosis of synaptic vesicles. J Cell Sci123: 595-605

[61] Linton MF, Gish R, Hubl ST (1991) Phenotypes of apolipoprotein B and apolipoprotein E after liver transplantation. J Clin Investig88: 270-281

[62] Liu Q, Zerbinatti CV, Zhang J, Hoe HS, Wang B, Cole SL (2007) Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron56: 66-78

[63] Liu B, Turley SD, Burns DK, Miller AM, Repa JJ, Dietschy JM (2009) Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1-/- mouse. Proc Natl Acad Sci106: 2377-2382

[64] Liu Q, Trotter J, Zhang J, Peters MM, Cheng H, Bao J (2010) Neuronal LRP1 knockout in adult mice leads to impaired brain lipid metabolism and progressive, age-dependent synapse loss and neurodegeneration. J Neurosci30: 17068-17078

[65] Lomnitski L, Oron L, Sklan D, Michaelson DM (1999) Distinct alterations in phospholipid metabolism in brains of apolipoprotein E-deficient mice. J Neurosci Res58: 586-592

[66] Lopez ME, Klein AD, Dimbil UJ, Scott MP (2011) Anatomically defined neuron-based rescue of neurodegenerative Niemann-Pick type C disorder. J Neurosci31: 4367-4378

[67] Lund EG, Guileyardo JM, Russell DW (1999) cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain. Proc Natl Acad Sci USA96(13): 7238-7243

[68] Lund EG, Xie C, Kotti T, Turley SD, Dietschy JM, Russell DW (2003) Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover. J Biol Chem25: 22980-22988

[69] Lütjohann D, Breuer O, Ahlborg G, Nennesmo I, Sidén A, Diczfalusy U, Björkhem I (1996) Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation. Proc Natl Acad Sci USA93: 9799-9804

[70] Madra M, Sturley SL(2010) Niemann-Pick type C pathogenesis and treatment: from statins to sugars. Clin Lipidol5: 387-395

[71] Mahley RW, Weisgraber KH, Huang Y (2006) Apolipopro- tein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc Natl Acad Sci USA103: 5644-5651

[72] Marquer C, Devauges V, Cossec JC, Liot G, Lecart S, Saudou F, Duyckaerts C, Leveque-Fort S, Potier MC (2011) Local cholesterol increase triggers amyloid precursor protein-BACE1 clustering in lipid rafts and rapid endocytosis. FASEB J25: 1295-1305

[73] Matsuda A, Nagao K, Matsuo M, Kioka N, Ueda K (2013) 24(S)- hydroxycholesterol is actively eliminated from neuronal cells by ABCA1. J Neurochem126: 93-101

[74] Mauch DH (2001) CNS synaptogenesis promoted by gliaderived cholesterol. Science294: 1354-1357

[75] Meaney S, Bodin K, Diczfalusy U, Bjorkhem I (2002) On the rate of translocation in vitro and kinetics in vivo of the major oxysterols in human circulation: critical importance of the position of the oxygen function. J Lipid Res43: 2130-2135

[76] Minagawa H, Gong JS, Jung CG, Watanabe A, Lund-Katz S, Phillips MC (2009) Mechanism underlying apolipoprotein E (ApoE) isoform-dependent lipid efflux from neural cells in culture. J Neurosci Res87: 2498-2508

[77] Morell P, Jurevics H (1996) Origin of cholesterol in myelin. Neurochemical Research21: 463-470

[78] Naureckiene S, Sleat D, Lackland H, Fensom A, Vanier MT, Wattiaux R (2000) Identification of HE1 as the second gene of Niemann-Pick C disease. Science290: 2298-2301

[79] Nieweg K, Schaller H, Pfrieger FW (2009) Marked differences in cholesterol synthesis between neurons and glial cells from postnatal rats. J Neurochem109: 125-134

[80] Nohturfft A, Yabe D, Goldstein JL, Brown MS, Espenshade PJ (2000) Regulated step in cholesterol feedback localized to budding of SCAP from ER membranes. Cell102: 315-323

[81] Numakawa T, Suzuki S, Kumamaru E, Adachi N, Richards M, Kunugi H (2010) BDNF function and intracellular signaling in neurons. Histol Histopathol25: 237-258

[82] Ollila S, Hyvönen MT, Vattulainen I (2007) Polyunsatu- ration in lipid membranes: dynamic properties and lateral pressure profiles. J Phys Chem B111: 3139-3150

[83] Ong WY, Sundaram RK, Huang E, Ghoshal S, Kumar U, Pentchev PG (2004) Neuronal localization and association of Niemann Pick C2 protein (HE1/ NPC2) with the postsynaptic density. Neuroscience128: 561-570

[84] Oram JF, Heinecke JW (2005) ATP-binding cassette transporter A1: a cell cholesterol exporter that protects against cardiovascular disease. Physiol Rev85: 1343-1372

[85] Panzenboeck U, Balazs Z, Sovic A, Hrzenjak A, Levak-Frank S, Wintersperger A (2002) ABCA1 and scavenger receptor class B, type I, are modulators of reverse sterol transport at an in vitro blood–brain barrier constituted of porcine brain capillary endothelial cells. J Biol Chem277: 42781-42789

[86] Patel SC, Suresh S, Kumar U, Hu CY, Cooney A, Blanchette-Mackie EJ (1999) Localization of Niemann-Pick C1 protein in astrocytes: implications for neuronal degeneration in Niemann- Pick type C disease. Proc Natl Acad Sci USA96: 1657-1662

[87] Pfenninger KH (2009) Plasma membrane expansion: a neuron’s Herculean task. Nat Rev Neurosci10: 251-261

[88] Pfrieger FW, Barres BA (1997) Synaptic efficacy enhanced by glial cells in vitro. Science277: 1684-1687

[89] Pfrieger FW, Ungerer N (2011) Cholesterol metabolism in neurons and astrocytes. Prog Lipid Res50: 357-371

[90] Piedrahita JA, Zhang SH, Hagaman JR, Oliver PM, Maeda N (1992) Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. Proc Natl Acad Sci USA89: 4471-4475

[91] Pitas RE, Boyles JK, Lee SH, Hui D, Weisgraber KH (1987a) Lipoproteins and their receptors in the central nervous system. Characterization of the lipoproteins in cerebrospinal fluid and identification of apolipoprotein B, E(LDL) receptors in the brain. J Biol Chem262: 14352-14360

[92] Pitas RE, Boyles JK, Lee SH (1987b) Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E- containing lipoproteins. Biochimi et Biophys Acta917: 148-161

[93] Plump AS, Smith JD, Hayek T, Aalto-Setala K, Walsh A, Verstuyft JG (1992) Severe hypercholesterolemia and atherosclerosis in apolipoprotein E- deficient mice created by homologous recombination in ES cells. Cell71: 343-353

[94] Pooler AM, Xi SC, Wurtman RJ (2006) The 3- hydroxy-3-methylglutaryl co-enzyme A reductase inhibitor pravastatin enhances neurite outgrowth in hippocampal neurons. J Neurochem97: 716-723

[95] Pottier C, Hannequin D, Coutant S (2012) High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Mol Psychiarty17: 875-879

[96] Prasad A, Fischer WA, Maue RA, Henderson LP (2000) Regional and developmental expression of the Npc1 mRNA in the mouse brain. J Neurochem75: 1250-1257

[97] Puglielli L, Tanzi RE, Kovacs DM (2003) Alzheimer’s disease: the cholesterol connection. Nat Neurosci6: 345-351

[98] Quan G, Xie C, Dietschy JM, Turley SD (2003) Ontogenesis and regulation of cholesterol metabolism in the central nervous system of the mouse. Brain Res Dev Brain Res146: 87-98

[99] Radhakrishnan A, Ikeda Y, Kwon HJ, Brown MS, Goldstein JL (2007) Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: oxysterols block transport by binding to Insig. Proc Natl Acad Sci104: 6511-6518

[100] Ramirez DM, Andersson S, Russell DW (2008) Neuronal expression and subcellular localization of cholesterol 24-hydroxylase in the mouse brain. J Comp Neurol507: 1676-1693

[101] Rebeck GW (2004) Cholesterol efflux as a critical component of Alzheimer’s disease pathogenesis. J Mol Neurosci23: 219-224

[102] Rebeck GW, Reiter JS, Strickland DK, Hyman BT (1993) Apolipoprotein E in sporadic Alzheimer’s disease: allelic variation and receptor interactions. Neuron11: 575-580

[103] Reid PC, Sakashita N, Sugii S, Ohno-Iwashita Y, Shimada Y, Hickey WF (2004) A novel cholesterol stain reveals early neuronal cholesterol accumulation in the Niemann-Pick type C1 mouse brain. J Lipid Res45: 582-591

[104] Roheim PS, Carey M, Forte T, Vega GL (1979) Apolipoproteins in human cerebrospinal fluid. Proc Natl Acad Sci USA76: 646-649

[105] Saher G, Brügger B, Lappe-Siefke C (2005) High cholesterol level is essential for myelin membrane growth. Nature Neuroscience8: 468-475

[106] Saito K, Dubreuil V, Arai Y, Wilsch-Brauninger M, Schwudke D, Saher G (2009) Ablation of cholesterol biosynthesis in neural stem cells increases their VEGF expression and angiogenesis but causes neuron apoptosis. Proc Natl Acad Sci106: 8350-8355

[107] Sakashita N, Miyazaki A, Takeya M, Horiuchi S, Chang CC, Chang TY (2000) Localization of human acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT-1) in macrophages and in various tissues. Am J Pathol156: 227-236

[108] Schmechel DE, Saunders AM, Strittmatter WJ (1993) Increased amyloid β-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci90: 9649-9653

[109] Schmitz G, Kaminski WE, Orso E (2000) ABC transporters in cellular lipid trafficking. Curr Opin Lipidol11: 493-501

[110] Snipes GJ, McGuire CB, Norden JJ, Freeman JA (1986) Nerve injury stimulates the secretion of apolipoprotein E by nonneuronal cells. Proc Natl Acad Sci USA83: 1130-1134

[111] Soccio RE, Breslow JL (2004) Intracellular cholesterol transport. Arterioscler Thromb Vasc Biol24: 1150-1160

[112] Storch J, Xu Z (2009) Niemann-Pick C2 (NPC2) and intracellular cholesterol trafficking. Biochim Biophys Acta1791: 671-678

[113] Tachikawa M, Watanabe M, Hori S, Fukaya M, Ohtsuki S, Asashima T, Terasaki T (2005) Distinct spatio-temporal expression of ABCA and ABCG transporters in the developing and adult mouse brain. J Neurochem95: 294-304

[114] Takamori S, Holt M, Stenius K, Lemke EA, Gronborg M, Riedel D (2006) Molecular anatomy of a trafficking organelle. Cell127: 831-846

[115] Tall AR (2008) Cholesterol efflux pathways and other potential mechanisms involved in the athero-protective effect of high density lipoproteins. J Intern Med263: 256-273

[116] Tarr PT, Edwards PA (2008) ABCG1 and ABCG4 are coexpressed in neurons and astrocytes of the CNS and regulate cholesterol homeostasis through SREBP-2. J Lipid Res49: 169-182

[117] Thelen KM, Falkai P, Bayer TA, Lütjohann D (2006) Cholesterol synthesis rate in human hippocampus declines with aging. Neurosci Lett403: 15-19

[118] Ullian EM, Sapperstein SK, Christopherson KS, Barres BA (2001) Control of synapse number by glia. Science291: 657-661

[119] Valdez CM, Smith MA, Perry G, Phelix CF, Santamaria F (2010) Cholesterol homeostasismarkers are localized tomouse hippocampal pyramidal and granule layers. Hippocampus20: 902-905

[120] Vance JE, Pan D, Campenot RB, Bussiere M, Vance DE (1994) Evidence that the major membrane lipids, except cholesterol, are made in axons of cultured rat sympathetic neurons. J Neurochem62: 329-337

[121] Vaughan AM, Oram JF (2006) ABCA1 and ABCG1 or ABCG4 act sequentially to remove cellular cholesterol and generate cholesterol- rich HDL. J Lipid Res47: 2433-2443

[122] Wahrle SE, Jiang H, Parsadanian M (2004) ABCA1 is required for normal central nervous system apoE levels and for lipidation of astrocyte-secreted apoE. J Biol Chem279: 40987-40993

[123] Wang Q, Yan J, Chen X, Li J, Yang Y, Weng J (2011) Statins: multiple neuroprotective mechanisms in neurodegenerative diseases. Exp Neurol230: 27-34

[124] Wellington CL, Walker EK, Suarez A, Kwok A, Bissada N, Singaraja R (2002) ABCA1 mRNA and protein distribution patterns predict multiple different roles and levels of regulation. Lab Invest82: 273-283

[125] Wollmer MA, Streffer JR, Tsolaki M, Grimaldi LM, Lutjohann D, Thal D (2003a) Genetic association of acyl-coenzyme A: cholesterol acyltransferase with cerebrospinal fluid cholesterol levels, brain amyloid load, and risk for Alzheimer’s disease. Mol Psychiatry8: 635-638

[126] Wollmer MA, Streffer JR, Lutjohann D, Tsolaki M, Iakovidou V, Hegi T (2003b) ABCA1 modulates CSF cholesterol levels and influences the age at onset of Alzheimer’s disease. Neurobiol Aging24: 421-426

[127] Wustner D, Mondal M, Tabas I, Maxfield FR (2005) Direct observation of rapid internalization and intracellular transport of sterol by macrophage foam cells. Traffic6: 396-412

[128] Xiong H, Callaghan D, Jones A, Walker DG, Lue LF, Beach TG, Sue LI, Woulfe J, Xu H, Stanimirovic DB (2008) Cholesterol retention in Alzheimer’s brain is responsible for high beta- and gamma-secretase activities and A-beta production. Neurobiol Dis29: 422-437

[129] Xu PT, Gilbert JR, Qiu HL, Ervin J, Rothrock-Christian TR, Hulette C, Schmechel DE (1999) Specificregional transcription of apolipoprotein E in human brain neurons. Am J Pathol154: 601-611

[130] Xu X, Bittman R, Duportail G, Heissler D, Vilcheze C, London E (2001) Effect of the structure of natural sterols and sphingolipids on the formation of ordered sphingolipid/ sterol domains (rafts). Comparison of cholesterol to plant, fungal, and disease-associated sterols and comparison of sphingomyelin, cerebrosides, and ceramide. J Biol Chem276: 33540-33546

RIGHTS & PERMISSIONS

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.