Cholesterol metabolism and homeostasis in the brain

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 Lett 269:15–18 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 Neurol 184:887–903 Berg JM (2002) The complex regulation of cholesterol biosynthesis takes place at several levels. Biochemistry, 5th edn. W.H. Freeman, New York Björkhem I (2006) Crossing the barrier: oxysterols as cholesterol transporters and metabolic modulators in the brain. J Intern Med 260:493–508 Björkhem I, Meaney S, Fogelman AM (2004) Brain cholesterol: long secret life behind a barrier. Arterioscler Thromb Vasc Biol 24:806–815 Björkhem I, Heverin M, Leoni V, Meaney S, Dicz-falusy U (2006) Oxysterols and Alzheimer’s disease. Acta Neurol Scand 114:43–49 Block RC, Dorsey ER, Beck CA, Brenna JT, Shoulson I (2010) Altered cholesterol and fatty acid metabolism in Huntington disease. J Clin Lipidol 4:17–23 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 Chem 265:17805–17815 Brown MS, Goldstein JL (1999) A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc Natl Acad Sci 96:11041–11048 Bryleva EY, Rogers MA, Chang CC, Buen F, Harris BT, Rousselet E et al (2010) ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD. Proc Natl Acad Sci 107:3081–3086 Cahoy JD et al (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 28:264–278 Carstea ED, Morris JA, Coleman KG, Loftus SK, Zhang D, Cummings C et al (1997) Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science 277:228–231 Christopherson KS et al (2005) Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120:421–433 Corder EH, Saunders AM, Strittmatter WJ et al (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923 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 USA 101:2070–2075 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 Chem 272:30766–30773 Dean M, Hamon Y, Chimini G (2001) The human ATP-binding cassette (ABC) transporter superfamily. J Lipid Res 42:1007–1017 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. Cell 99:703–712 DeGrella RF, Simoni RD (1982) Intracellular transport of cholesterol to the plasma membrane. J Biol Chem 257:14256–14262 Di Paolo G, Kim TW (2011) Linking lipids to Alzheimer’s disease: cholesterol and beyond. Nat Rev Neurosci 12:284–296 Dietschy JM, Turley SD (2004) Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res 45:1375–1397 Elrick MJ, Pacheco CD, Yu T, Dadgar N, Shakkottai VG, Ware C et al (2010) Conditional Niemann-Pick C mice demonstrate cell autonomous Purkinje cell neurodegeneration. Hum Mol Genet 19:837–847 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 Tech 50:297–304 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 Chem 271:30121–30125 Fester L, Zhou L, Bütow A (2009) Cholesterol-promoted synaptogenesis requires the conversion of cholesterol to estradiol in the hippocampus. Hippocampus 19:692–705 Fox MA, Umemori H (2006) Seeking long-term relationship: axon and target communicate to organize synaptic differentiation. J Neurochem 97:1215–1231 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 Chem 277:48508–48513 Fünfschilling U, Saher G, Xiao L, Möbius W, Nave KA (2007) Survival of adult neurons lacking cholesterol synthesis in vivo. BMC Neurosci 2:1–8 Gelissen IC, Harris M, Rye KA, Quinn C, Brown AJ, Kockx M et al (2006) ABCA1 and ABCG1 synergize to mediate cholesterol export to apoA-I. Arterioscler Thromb Vasc Biol 26:534–540 German DC, Liang CL, Song T, Yazdani U, Xie C, Dietschy JM (2002) Neurodegeneration in the Niemann-Pick C mouse: glial involvement. Neuroscience 109:437–450 Goritz C, Mauch DH, Pfrieger FW (2005) Multiple mechanisms mediate cholesterol-induced synaptogenesis in a CNS neuron. Mol Cell Neurosci 29:190–201 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 Res 1249:34–42 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 Chem 278:8043–8051 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 Sci 97:8375–8380 Herz J (2009) Apolipoprotein E receptors in the nervous system”. Curr Opin Lipidol 20:190–196 Hirsch-Reinshagen V, Zhou S, Burgess BL, Bernier L, McIsaac SA, Chan JY et al (2004) Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain. J Biol Chem 279:41197–41207 Hirsch-Reinshagen V, Maia LF, Burgess BL et al (2005) The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease. J Biol Chem 280:43243–43256 Hu CY, Ong WY, Patel SC (2000) Regional distribution of NPC1 protein in monkey brain. J Neurocytol 29:765–773 Hutter-Paier B, Huttunen HJ, Puglielli L, Eckman CB, Kim DY, Hofmeister A et al (2004) The ACAT inhibitor CP-113, 818 markedly reduces amyloid pathology in a mouse model of Alzheimer’s disease. Neuron 44:227–238 Ignatius MJ, Gebicke-Harter PJ, Skene JH, Schilling JW, Weis-grabber KH, Mahley RW, Shooter EM (1986) Expression of apolipoprotein E during nerve degeneration and regeneration. Proc Natl Acad Sci USA 83:1125–1129 Ignatius MJ, Shooter EM, Pitas RE, Mahley RW (1987) Lipoprotein uptake by neuronal growth cones in vitro. Science 236:950–962 Ikonen E (2008) Cellular cholesterol trafficking and compartmentalization. Nat Rev Mol Cell Biol 9:125–138 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 Sci 96:266–271 Jansen PJ, Lutjohann D, Thelen KM, von Bergmann K, van Leuven F, Ramaekers FC et al (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 Dis 18:319–329 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 Res 21:364–376 Jurevics H, Morell P (1995) Cholesterol for synthesis of myelin is made locally, not imported into brain. J Neurochem 64:895–901 Jurevics HA, Kidwai FZ, Morell P (1997) Sources of cholesterol during development of the rat fetus and fetal organs. J Lipid Res 38:723–733 Kaplan MR, Simoni RD (1985) Transport of cholesterol from the endoplasmic reticulum to the plasma membrane. J Cell Biol 101:446–453 Karten B, Campenot RB, Vance DE, Vance JE (2006) Expression of ABCG1, but not ABCA1, correlates with cholesterol release by cerebellar astroglia. J Biol Chem 281:4049–4057 Kim WS, Weickert CS, Garner B (2008) Role of ATP-binding cassette transporters in brain lipid transport and neurological disease. J Neurochem 104:1145–1166 Ko M, Zou K, Minagawa H et al (2005) Cholesterol-mediated neurite outgrowth is differently regulated between cortical and hippocampal neurons. J Biol Chem 52:42759–42765 Koch S, Donarski N, Goetze K, Kreckel M, Stuerenburg HJ, Buhmann C et al (2001) Characterization of four lipoprotein classes in human cerebrospinal fluid. J Lipid Res 42:1143–1151 Koldamova RP, Lefterov IM, Ikonomovic MD, Skoko J, Lefterov PI, Isanski BA et al (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 Chem 278:13244–13256 Korade Z, Kenworthy AK (2008) Lipid rafts, cholesterol, and the brain. Neuropharmacology 55:1265–1273 Lahiri DK (2004) ApolipoproteinEasatargetfordevelopingnew therapeutics for Alzheimer’s disease based on studies from protein, the gene. J Mol Neurosci 23:225–233 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 Res 36:1092–1097 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 Neurochem 95:987–997 Li Y, Lu W, Marzolo MP, Bu G (2001) Differential functions of mem- bers of the low density lipoprotein receptor family suggested by their distinct endocytosis rates. J Biol Chem 276:18000–18006 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 NeuroChem 88:623–634 Linetti A, Fratangeli A, Taverna E, Valnegri P, Francolini M, Cappello V et al (2010) Cholesterol reduction impairs exocytosis of synaptic vesicles. J Cell Sci 123:595–605 Linton MF, Gish R, Hubl ST et al (1991) Phenotypes of apolipoprotein B and apolipoprotein E after liver transplantation. J Clin Investig 88:270–281 Liu Q, Zerbinatti CV, Zhang J, Hoe HS, Wang B, Cole SL et al (2007) Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron 56:66–78 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 Sci 106:2377–2382 Liu Q, Trotter J, Zhang J, Peters MM, Cheng H, Bao J et al (2010) Neuronal LRP1 knockout in adult mice leads to impaired brain lipid metabolism and progressive, age-dependent synapse loss and neurodegeneration. J Neurosci 30:17068–17078 Lomnitski L, Oron L, Sklan D, Michaelson DM (1999) Distinct alterations in phospholipid metabolism in brains of apolipoprotein E-deficient mice. J Neurosci Res 58:586–592 Lopez ME, Klein AD, Dimbil UJ, Scott MP (2011) Anatomically defined neuron-based rescue of neurodegenerative Niemann-Pick type C disorder. J Neurosci 31:4367–4378 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 USA 96(13):7238–7243 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 Chem 25:22980–22988 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 USA 93:9799–9804 Madra M, Sturley SL (2010) Niemann-Pick type C pathogenesis and treatment: from statins to sugars. Clin Lipidol 5:387–395 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 USA 103:5644–5651 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 J 25:1295–1305 Matsuda A, Nagao K, Matsuo M, Kioka N, Ueda K (2013) 24(S)-hydroxycholesterol is actively eliminated from neuronal cells by ABCA1. J Neurochem 126:93–101 Mauch DH et al (2001) CNS synaptogenesis promoted by glia-derived cholesterol. Science 294:1354–1357 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 Res 43:2130–2135 Minagawa H, Gong JS, Jung CG, Watanabe A, Lund-Katz S, Phillips MC et al (2009) Mechanism underlying apolipoprotein E (ApoE) isoform-dependent lipid efflux from neural cells in culture. J Neurosci Res 87:2498–2508 Morell P, Jurevics H (1996) Origin of cholesterol in myelin. Neurochemical Research 21:463–470 Naureckiene S, Sleat D, Lackland H, Fensom A, Vanier MT, Wattiaux R et al (2000) Identification of HE1 as the second gene of Niemann-Pick C disease. Science 290:2298–2301 Nieweg K, Schaller H, Pfrieger FW (2009) Marked differences in cholesterol synthesis between neurons and glial cells from postnatal rats. J Neurochem 109:125–134 Nohturfft A, Yabe D, Goldstein JL, Brown MS, Espenshade PJ (2000) Regulated step in cholesterol feedback localized to budding of SCAP from ER membranes. Cell 102:315–323 Numakawa T, Suzuki S, Kumamaru E, Adachi N, Richards M, Kunugi H (2010) BDNF function and intracellular signaling in neurons. Histol Histopathol 25:237–258 Ollila S, Hyvo ̈nen MT, Vattulainen I (2007) Polyunsatu- ration in lipid membranes: dynamic properties and lateral pressure profiles. J Phys Chem B 111:3139–3150 Ong WY, Sundaram RK, Huang E, Ghoshal S, Kumar U, Pentchev PG et al (2004) Neuronal localization and association of Niemann Pick C2 protein (HE1/ NPC2) with the postsynaptic density. Neuroscience 128:561–570 Oram JF, Heinecke JW (2005) ATP-binding cassette transporter A1: a cell cholesterol exporter that protects against cardiovascular disease. Physiol Rev 85:1343–1372 Panzenboeck U, Balazs Z, Sovic A, Hrzenjak A, Levak-Frank S, Wintersperger A et al (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 Chem 277:42781–42789 Patel SC, Suresh S, Kumar U, Hu CY, Cooney A, Blanchette-Mackie EJ et al (1999) Localization of Niemann-Pick C1 protein in astrocytes: implications for neuronal degeneration in Niemann- Pick type C disease. Proc Natl Acad Sci USA 96:1657–1662 Pfenninger KH (2009) Plasma membrane expansion: a neuron’s Herculean task. Nat Rev Neurosci 10:251–261 Pfrieger FW, Barres BA (1997) Synaptic efficacy enhanced by glial cells in vitro. Science 277:1684–1687 Pfrieger FW, Ungerer N (2011) Cholesterol metabolism in neurons and astrocytes. Prog Lipid Res 50:357–371 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 USA 89:4471–4475 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 Chem 262:14352–14360 Pitas RE, Boyles JK, Lee SH (1987b) Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E- containing lipoproteins. Biochimi et Biophys Acta 917:148–161 Plump AS, Smith JD, Hayek T, Aalto-Setala K, Walsh A, Verstuyft JG et al (1992) Severe hypercholesterolemia and atherosclerosis in apolipoprotein E- deficient mice created by homologous recombination in ES cells. Cell 71:343–353 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 Neurochem 97:716–723 Pottier C, Hannequin D, Coutant S et al (2012) High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Mol Psychiarty 17:875–879 Prasad A, Fischer WA, Maue RA, Henderson LP (2000) Regional and developmental expression of the Npc1 mRNA in the mouse brain. J Neurochem 75:1250–1257 Puglielli L, Tanzi RE, Kovacs DM (2003) Alzheimer’s disease: the cholesterol connection. Nat Neurosci 6:345–351 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 Res 146:87–98 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 Sci 104:6511–6518 Ramirez DM, Andersson S, Russell DW (2008) Neuronal expression and subcellular localization of cholesterol 24-hydroxylase in the mouse brain. J Comp Neurol 507:1676–1693 Rebeck GW (2004) Cholesterol efflux as a critical component of Alzheimer’s disease pathogenesis. J Mol Neurosci 23:219–224 Rebeck GW, Reiter JS, Strickland DK, Hyman BT (1993) Apolipoprotein E in sporadic Alzheimer’s disease: allelic variation and receptor interactions. Neuron 11:575–580 Reid PC, Sakashita N, Sugii S, Ohno-Iwashita Y, Shimada Y, Hickey WF et al (2004) A novel cholesterol stain reveals early neuronal cholesterol accumulation in the Niemann-Pick type C1 mouse brain. J Lipid Res 45:582–591 Roheim PS, Carey M, Forte T, Vega GL (1979) Apolipoproteins in human cerebrospinal fluid. Proc Natl Acad Sci USA 76:646–649 Saher G, Brügger B, Lappe-Siefke C et al (2005) High cholesterol level is essential for myelin membrane growth. Nature Neuroscience 8:468–475 Saito K, Dubreuil V, Arai Y, Wilsch-Brauninger M, Schwudke D, Saher G et al (2009) Ablation of cholesterol biosynthesis in neural stem cells increases their VEGF expression and angiogenesis but causes neuron apoptosis. Proc Natl Acad Sci 106:8350–8355 Sakashita N, Miyazaki A, Takeya M, Horiuchi S, Chang CC, Chang TY et al (2000) Localization of human acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT-1) in macrophages and in various tissues. Am J Pathol 156:227–236 Schmechel DE, Saunders AM, Strittmatter WJ et al (1993) Increased amyloid β-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci 90:9649–9653 Schmitz G, Kaminski WE, Orso E (2000) ABC transporters in cellular lipid trafficking. Curr Opin Lipidol 11:493–501 Snipes GJ, McGuire CB, Norden JJ, Freeman JA (1986) Nerve injury stimulates the secretion of apolipoprotein E by nonneuronal cells. Proc Natl Acad Sci USA 83:1130–1134 Soccio RE, Breslow JL (2004) Intracellular cholesterol transport. Arterioscler Thromb Vasc Biol 24:1150–1160 Storch J, Xu Z (2009) Niemann-Pick C2 (NPC2) and intracellular cholesterol trafficking. Biochim Biophys Acta 1791:671–678 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 Neurochem 95:294–304 Takamori S, Holt M, Stenius K, Lemke EA, Gronborg M, Riedel D et al (2006) Molecular anatomy of a trafficking organelle. Cell 127:831–846 Tall AR (2008) Cholesterol efflux pathways and other potential mechanisms involved in the athero-protective effect of high density lipoproteins. J Intern Med 263:256–273 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 Res 49:169–182 Thelen KM, Falkai P, Bayer TA, Lütjohann D (2006) Cholesterol synthesis rate in human hippocampus declines with aging. Neurosci Lett 403:15–19 Ullian EM, Sapperstein SK, Christopherson KS, Barres BA (2001) Control of synapse number by glia. Science 291:657–661 Valdez CM, Smith MA, Perry G, Phelix CF, Santamaria F (2010) Cholesterol homeostasis markers are localized to mouse hippocampal pyramidal and granule layers. Hippocampus 20:902–905 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 Neurochem 62:329–337 Vaughan AM, Oram JF (2006) ABCA1 and ABCG1 or ABCG4 act sequentially to remove cellular cholesterol and generate cholesterol-rich HDL. J Lipid Res 47:2433–2443 Wahrle SE, Jiang H, Parsadanian M et al (2004) ABCA1 is required for normal central nervous system apoE levels and for lipidation of astrocyte-secreted apoE. J Biol Chem 279:40987–40993 Wang Q, Yan J, Chen X, Li J, Yang Y, Weng J et al (2011) Statins: multiple neuroprotective mechanisms in neurodegenerative diseases. Exp Neurol 230:27–34 Wellington CL, Walker EK, Suarez A, Kwok A, Bissada N, Singaraja R et al (2002) ABCA1 mRNA and protein distribution patterns predict multiple different roles and levels of regulation. Lab Invest 82:273–283 Wollmer MA, Streffer JR, Tsolaki M, Grimaldi LM, Lutjohann D, Thal D et al (2003a) Genetic association of acyl-coenzyme A: cholesterol acyltransferase with cerebrospinal fluid cholesterol levels, brain amyloid load, and risk for Alzheimer’s disease. Mol Psychiatry 8:635–638 Wollmer MA, Streffer JR, Lutjohann D, Tsolaki M, Iakovidou V, Hegi T et al (2003b) ABCA1 modulates CSF cholesterol levels and influences the age at onset of Alzheimer’s disease. Neurobiol Aging 24:421–426 Wustner D, Mondal M, Tabas I, Maxfield FR (2005) Direct observation of rapid internalization and intracellular transport of sterol by macrophage foam cells. Traffic 6:396–412 Xiong H, Callaghan D, Jones A, Walker DG, Lue LF, Beach TG, Sue LI, Woulfe J, Xu H, Stanimirovic DB et al (2008) Cholesterol retention in Alzheimer’s brain is responsible for high beta- and gamma-secretase activities and A-beta production. Neurobiol Dis 29:422–437 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 Pathol 154:601–611 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 Chem 276:33540–33546