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Why lipids are important for Alzheimer disease?

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Abstract

Several lines of evidence suggest that dysregulated lipid metabolism may participate in the pathogenesis of Alzheimer’s disease (AD). Epidemiologic studies suggest that elevated mid-life plasma cholesterol levels may be associated with an increased risk of AD and that statin use may reduce the prevalence of AD. Cellular studies have shown that the levels and distribution of intracellular cholesterol markedly affect the processing of amyloid precursor protein into Aβ peptides, which are the toxic species that accumulate as amyloid plaques in the AD brain. Most importantly, genetic evidence identifies apolipoprotein E, the major cholesterol carrier in the central nervous system, as the primary genetic risk factor for sporadic AD. In humans, apoE exists as three major alleles (apoE2, apoE3, and apoE4), and inheritance of the apoE4 allele increases the risk of developing AD at an earlier age. However, exactly how apoE functions in the pathogenesis of AD remains to be fully determined. Our studies have identified that the cholesterol transporter ABCA1 is a crucial regulator of apoE levels and lipidation in the brain. Deficiency of ABCA1 leads to the loss of approximately 80% of apoE in the brain, and the residual 20% that remains is poorly lipidated. Several independent studies have shown this poorly lipidated apoE increases amyloid burden in mouse models of AD, demonstrating that apoE lipidation by ABCA1 affects key steps in amyloid deposition or clearance. Conversely, robust overexpression of ABCA1 in the brain promotes apoE lipidation and nearly eliminates the formation of mature amyloid plaques. These studies show that the lipid binding capacity of apoE is a major mechanism of its function in the pathogenesis of AD, and suggest that increasing apoE lipidation may be of therapeutic importance for this devastating disease.

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References

  1. Price DL, Tanzi RE, Borchelt DR et al (1998) Alzheimer’s disease: genetic studies and transgenic models. Annu Rev Genet 32:461–493. doi:10.1146/annurev.genet.32.1.461

    PubMed  CAS  Google Scholar 

  2. McKhann G, Drachman D, Folstein M et al (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA work group under the auspices of the department of health and human services task force on Alzheimer’s disease. Neurology 34:939–944

    PubMed  CAS  Google Scholar 

  3. Morris JC (1997) Clinical assessment of Alzheimer’s disease. Neurology 49(Suppl):S7–S10

    PubMed  CAS  Google Scholar 

  4. Dietschy JM, Turley SD (2001) Cholesterol metabolism in the brain. Curr Opin Lipidol 12:105–112. doi:10.1097/00041433-200104000-00003

    PubMed  CAS  Google Scholar 

  5. Björkhem I, Lütjohann D, Diczfalusy U (1998) Cholesterol homeostasis in the human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation. J Lipid Res 39:1594–1600

    PubMed  Google Scholar 

  6. Björkhem I, Lütjohann D, Breuer O et al (1997) Importance of a novel oxidative mechanism for elimination of brain cholesterol. J Biol Chem 272:30178–30184. doi:10.1074/jbc.272.48.30178

    PubMed  Google Scholar 

  7. Pitas RE, Boyles JK, Lee SH et al (1987) Lipoproteins and their receptors in the central nervous system. J Biol Chem 262:14352–14360

    PubMed  CAS  Google Scholar 

  8. Ladu MJ, Reardon C, Van Eldik L et al (2000) Lipoproteins in the central nervous system. Ann NY Acad Sci 903:167–175. doi:10.1111/j.1749-6632.2000.tb06365.x

    PubMed  CAS  Google Scholar 

  9. Zannis VI, Breslow JL (1981) Human very low density lipoprotein apolipoprotein E isoprotein polymorphism is explained by genetic variation and posttranslational modification. Biochemistry 20:1033–1041. doi:10.1021/bi00507a059

    PubMed  CAS  Google Scholar 

  10. Weisgraber KH, Rall SC Jr, Mahley RW (1981) Human E apoprotein heterogeneity: cysteine-arginine interchanges in the amino acid sequence of the apo-E isoforms. J Biol Chem 256:9077–9083

    PubMed  CAS  Google Scholar 

  11. Corder EH, Saunders AM, Strittmatter WJ et al (1993) Gene dose of apolipoprotein E type 4 and the risk of Alzheimer’s disease in late onset families. Science 261:921–923. doi:10.1126/science.8346443

    PubMed  CAS  Google Scholar 

  12. Saunders AM, Strittmatter WJ, Schmechel D et al (1993) Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43:1467–1472

    PubMed  CAS  Google Scholar 

  13. Strittmatter WJ, Roses AD (1995) Apolipoprotein E and Alzheimer disease. Proc Natl Acad Sci USA 92:4725–4727. doi:10.1073/pnas.92.11.4725

    PubMed  CAS  Google Scholar 

  14. Corder EH, Saunders AM, Risch NJ et al (1994) Protective effect of apolipoprotein E type 2 for late onset Alzheimer disease. Nat Genet 7:180–184. doi:10.1038/ng0694-180

    PubMed  CAS  Google Scholar 

  15. Tokuda T, Calero M, Matsubara E et al (2000) Lipidation of apolipoprotein E influences its isoform-specific interaction with Alzheimer’s amyloid β peptides. Biochem J 348:359–365. doi:10.1042/0264-6021:3480359

    PubMed  CAS  Google Scholar 

  16. Ladu MJ, Pederson TM, Frail DE et al (1995) Purification of apolipoprotein E attenuates isoform-specific binding to beta-amyloid. J Biol Chem 270:9039–9042. doi:10.1074/jbc.270.16.9039

    PubMed  CAS  Google Scholar 

  17. Ladu MJ, Falduto MT, Manelli AM et al (1994) Isoform-specific binding of apolipoprotein E to beta-amyloid. J Biol Chem 269:23403–23406

    PubMed  CAS  Google Scholar 

  18. Aleshkov S, Abraham CR, Zannis VI (1997) Interaction of nascent ApoE2, ApoE3, and ApoE4 isoforms expressed in mammalian cells with amyloid peptide β (1–40): Relevance to Alzheimer’s disease. Biochemistry 36:10571–10580. doi:10.1021/bi9626362

    PubMed  CAS  Google Scholar 

  19. Zhou Z, Smith JD, Greengard P et al (1996) Alzheimer amyloid-beta peptide forms denaturant-resistant complex with type epsilon 3 but not type epsilon 4 isoform of native apolipoprotein E. Mol Med 2:175–180. doi:10.1007/s0089460020175

    PubMed  CAS  Google Scholar 

  20. Koistinaho M, Lin S, Wu X et al (2004) Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat Med 10:719–726. doi:10.1038/nm1058

    PubMed  CAS  Google Scholar 

  21. Cole GM, Ard MD (2000) Influence of lipoproteins on microglial degradation of Alzheimer’s amyloid beta-protein. Microsc Res Tech 50:316–324. doi:10.1002/1097-0029(20000815)50:4<316::AID-JEMT11>3.0.CO;2-E

    PubMed  CAS  Google Scholar 

  22. Holtzman DM, Fagan AM, Mackey B (2000) Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer’s disease model. Ann Neurol 47:739–747. doi:10.1002/1531-8249(200006)47:6<739::AID-ANA6>3.0.CO;2-8

    PubMed  CAS  Google Scholar 

  23. Bales KR, Verina T, Dodel R (1997) Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat Genet 17:263–264. doi:10.1038/ng1197-263

    PubMed  CAS  Google Scholar 

  24. Bales KR, Verina T, Cummins DJ et al (1999) Apolipoprotein E is essential for amyloid deposition in the APP (V717F) transgenic mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 96:15233–15238. doi:10.1073/pnas.96.26.15233

    PubMed  CAS  Google Scholar 

  25. Holtzman DM, Bales KR, Wu S (1999) Expression of human apolipoprotein E reduces amyloid-β deposition in a mouse model of Alzheimer’s disease. J Clin Invest 103:R15–R21. doi:10.1172/JCI6179

    PubMed  CAS  Google Scholar 

  26. Costa DA, Nilsson LN, Bales KR et al (2004) Apolipoprotein E is required for the formation of filamentous amyloid, but not for amorphous Abeta deposition, in an AbetaPP/PS double transgenic mouse model of Alzheimer’s disease. J Alzheimers Dis 6:509–514

    PubMed  CAS  Google Scholar 

  27. Irizarry MC, Rebeck GW, Cheung B et al (2000) Modulation of Aβ deposition in APP transgenic mice by an apolipoprotein E null background. Ann NY Acad Sci 920:171–178

    Article  PubMed  CAS  Google Scholar 

  28. Holtzman DM, Bales KR, Tenkova T et al (2000) Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 97:2892–2897. doi:10.1073/pnas.050004797

    PubMed  CAS  Google Scholar 

  29. Carter DB, Dunn E, McKinley DD et al (2001) Human apolipoprotein E4 accelerates beta-amyloid deposition in APPsw transgenic mouse brain. Ann Neurol 50:468–475. doi:10.1002/ana.1134

    PubMed  CAS  Google Scholar 

  30. Buttini M, Yu GQ, Shockley K et al (2002) Modulation of Alzheimer-like synaptic and cholinergic deficits in transgenic mice by human apolipoprotein E depends on isoform, aging, and overexpression of amyloid beta peptides but not on plaque formation. J Neurosci 22:10539–10548

    PubMed  CAS  Google Scholar 

  31. Dodart JC, Marr RA, Koistinaho M (2005) Gene delivery of human apolipoprotein E alters brain Abeta burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 102:1211–1216. doi:10.1073/pnas.0409072102

    PubMed  CAS  Google Scholar 

  32. Rebeck GW, Reiter JS, Strickland DK et al (1993) Apolipoprotein E in sporadic Alzheimer’s disease: allelic variation and receptor interactions. Neuron 11:575–580. doi:10.1016/0896-6273(93)90070-8

    PubMed  CAS  Google Scholar 

  33. Nagy Z, Esiri MM, Jobst KA et al (1995) Influence of the apolipoprotein E genotype on amyloid deposition and neurofibrillary tangle formation in Alzheimer’s disease. Neuroscience 69:757–761. doi:10.1016/0306-4522(95)00331-C

    PubMed  CAS  Google Scholar 

  34. 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 USA 90:9649–9653. doi:10.1073/pnas.90.20.9649

    PubMed  CAS  Google Scholar 

  35. Berg L, McKeel DW Jr, Miller JP et al (1998) Clinicopathologic studies in cognitively healthy aging and Alzheimer’s disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype. Arch Neurol 55:326–335. doi:10.1001/archneur.55.3.326

    PubMed  CAS  Google Scholar 

  36. Tiraboschi P, Hansen LA, Masliah E et al (2004) Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer disease. Neurology 62:1977–1983

    PubMed  CAS  Google Scholar 

  37. Bu G, Maksymovitch EA, Nerbonne JM et al (1994) Expression and function of the low density lipoprotein receptor-related protein (LRP) in mammalian central neurons. J Biol Chem 269:18521–18528

    PubMed  CAS  Google Scholar 

  38. Rebeck GW, Harr SD, Strickland DK et al (1995) Multiple, diverse senile plaque-associated proteins are ligands of an apolipoprotein E receptor, the alpha 2-macroglobulin receptor/low-density-lipoprotein receptor-related protein. Ann Neurol 37:211–217. doi:10.1002/ana.410370212

    PubMed  CAS  Google Scholar 

  39. Fryer JD, DeMattos RB, McCormick LM (2005) The low density lipoprotein receptor regulates the level of central nervous system human and murine apolipoprotein E but does not modify amyloid plaque pathology in PDAPP mice. J Biol Chem 280:25754–25759. doi:10.1074/jbc.M502143200

    PubMed  CAS  Google Scholar 

  40. Liu Q, Zerbinatti CV, Zhang J et al (2007) Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron 56:66–78. doi:10.1016/j.neuron.2007.08.008

    PubMed  CAS  Google Scholar 

  41. Shibata M, Yamada S, Kumar SR et al (2000) Clearance of Alzheimer’s amyloid-β 1–40 peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest 106:1489–1499. doi:10.1172/JCI10498

    PubMed  CAS  Google Scholar 

  42. Bell RD, Sagaare AP, Friedman AE et al (2006) Transport pathways for clearance of human Alzheimer’s amyloid β-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab 27:909–918

    PubMed  Google Scholar 

  43. Zlokovic BV, Martel CL, Matsubara E (1996) Glycoprotein 330/megalin: Probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer disease amyloid β at the blood-brain and blood-cerebrospinal fluid barriers. Proc Natl Acad Sci USA 93:4229–4234. doi:10.1073/pnas.93.9.4229

    PubMed  CAS  Google Scholar 

  44. Dean M, Allikmets R (2001) Complete characterization of the human ABC gene family. J Bioenerg Biomembr 33:475–479. doi:10.1023/A:1012823120935

    PubMed  CAS  Google Scholar 

  45. Dean M, Hamon Y, Chimini G (2001) The human ATP-binding cassette (ABC) transporter superfamily. J Lipid Res 42:1007–1017

    PubMed  CAS  Google Scholar 

  46. Schmitz G, Kaminski WE, Orsó E (2000) ABC transporters in cellular lipid trafficking. Curr Opin Lipidol 11:493–501. doi:10.1097/00041433-200010000-00007

    PubMed  CAS  Google Scholar 

  47. Puglielli L, Tanzi RE, Kovacs DM (2003) Alzheimer’s disease: the cholesterol connection. Nat Neurosci 6:345–351. doi:10.1038/nn0403-345

    PubMed  CAS  Google Scholar 

  48. Wahrle S, Das P, Nyborg AC et al (2002) Cholesterol-dependent γ-secretase activity in buoyant cholesterol-rich membrane microdomains. Neurobiol Dis 9:11–23. doi:10.1006/nbdi.2001.0470

    PubMed  CAS  Google Scholar 

  49. Burns M, Gaynor K, Olm V et al (2003) Presenilin redistribution associated with aberrant cholesterol transport enhances β-amyloid production in vivo. J Neurosci 23:5645–5649

    PubMed  CAS  Google Scholar 

  50. Shie FS, Jin LW, Cook DG et al (2002) Diet-induced hypercholesterolemia enhances brain A beta accumulation in transgenic mice. Neuroreport 213:455–459. doi:10.1097/00001756-200203250-00019

    Google Scholar 

  51. Refolo LM, Pappolla MA, Malester B (2000) Hypercholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model. Neurobiol Dis 7:321–331. doi:10.1006/nbdi.2000.0304

    PubMed  CAS  Google Scholar 

  52. Fassbender K, Simons M, Bergmann C et al (2001) Simvastatin strongly reduces levels of Alzheimer’s disease β-amyloid peptides Aβ42 and Aβ40 in vitro and in vivo. Proc Natl Acad Sci USA 98:5856–5861. doi:10.1073/pnas.081620098

    PubMed  CAS  Google Scholar 

  53. Kojro E, Gimple G, Lammich S et al (2001) Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10. Proc Natl Acad Sci USA 98:5815–5820. doi:10.1073/pnas.081612998

    PubMed  CAS  Google Scholar 

  54. Simons M, Keller P, De Strooper B et al (1998) Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neurons. Proc Natl Acad Sci USA 95:6460–6464. doi:10.1073/pnas.95.11.6460

    PubMed  CAS  Google Scholar 

  55. Bodovitz S, Klein WL (1996) Cholesterol modulates α-secretase cleavage of amyloid precursor protein. J Biol Chem 271:4436–4440. doi:10.1074/jbc.271.8.4436

    PubMed  CAS  Google Scholar 

  56. Buxbaum JD, Geoghagan NS, Friedhoff LT (2001) Cholesterol depletion with physiological concentrations of a statin decreases the formation of the Alzheimer amyloid Abeta peptide. J Alzheimers Dis 3:221–229

    PubMed  CAS  Google Scholar 

  57. Ehehalt R, Keller P, Haass C et al (2003) Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts. J Cell Biol 160:113–123. doi:10.1083/jcb.200207113

    PubMed  CAS  Google Scholar 

  58. Hayden MR, Clee SM, Brooks-Wilson A et al (2000) Cholesterol efflux regulatory protein, Tangier disease and familial high-density lipoprotein deficiency. Curr Opin Lipidol 11:117–122. doi:10.1097/00041433-200004000-00003

    PubMed  CAS  Google Scholar 

  59. Brooks-Wilson A, Marcil M, Clee SM et al (1999) Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet 22:336–345. doi:10.1038/11905

    PubMed  CAS  Google Scholar 

  60. Rust S, Rosier M, Funke H et al (1999) Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 22:352–355. doi:10.1038/11921

    PubMed  CAS  Google Scholar 

  61. Bodzioch M, Orsó E, Klucken J et al (1999) The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 22:347–351. doi:10.1038/11914

    PubMed  CAS  Google Scholar 

  62. Oram JF, Heinecke JW (2005) ATP-binding cassette transporter A1: a cell cholesterol exporter that protects against cardiovascular disease. Physiol Rev 85:1343–1372. doi:10.1152/physrev.00005.2005

    PubMed  CAS  Google Scholar 

  63. Wellington CL, Walker EK, Suarez A et al (2002) ABCA1 mRNA and protein distribution patterns predict multiple different roles and levels of regulation. Lab Invest 82:273–283

    PubMed  CAS  Google Scholar 

  64. Francis GA, Knopp RH, Oram JF (1995) Defective removal of cellular cholesterol and phospholipids by apolipoprotein A-I in Tangier disease. J Clin Invest 96:78–87. doi:10.1172/JCI118082

    PubMed  CAS  Google Scholar 

  65. Hirsch-Reinshagen V, Zhou S, Burgess BL et al (2004) Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain. J Biol Chem 279:41197–41207. doi:10.1074/jbc.M407962200

    PubMed  CAS  Google Scholar 

  66. Wahrle SE, Jiang H, Parsadanian M et al (2004) ABCA1 is required for normal CNS apoE levels and for lipidation of astrocyte-secreted apoE. J Biol Chem 279:40987–40993. doi:10.1074/jbc.M407963200

    PubMed  CAS  Google Scholar 

  67. Remaley AT, Stonick JA, Demosky SJ et al (2001) Apolipoprotein specificity for lipid efflux by the human ABCA1 transporter. Biochem Biophys Res Commun 280:818–823. doi:10.1006/bbrc.2000.4219

    PubMed  CAS  Google Scholar 

  68. Wahrle S, Jiang H, Parsadanian M et al (2005) Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease. J Biol Chem 280:43236–43242. doi:10.1074/jbc.M508780200

    PubMed  CAS  Google Scholar 

  69. 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’s disease. J Biol Chem 280:43243–43256. doi:10.1074/jbc.M508781200

    PubMed  CAS  Google Scholar 

  70. Koldamova R, Staufenbiel M, Lefterov I (2005) Lack of ABCA1 considerably decreased brain apoE level and increases amyloid deposition in APP23 mice. J Biol Chem 280:43224–43235. doi:10.1074/jbc.M504513200

    PubMed  CAS  Google Scholar 

  71. Burns MP, Vardanian L, Pajoohesh-Gangi A (2006) The effects of ABCA1 on cholesterol efflux and Aβ levels in vitro and in vivo. J Neurochem 98:792–800. doi:10.1111/j.1471-4159.2006.03925.x

    PubMed  CAS  Google Scholar 

  72. Sun Y, Yao J, Kim T-W et al (2003) Expression of LXR target genes decreases cellular amyloid β peptide secretion. J Biol Chem 278:27688–27694. doi:10.1074/jbc.M300760200

    PubMed  CAS  Google Scholar 

  73. Koldamova RP, Lefterov IM, Ikonomovic MD 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 β secretion. J Biol Chem 278:13244–13256. doi:10.1074/jbc.M300044200

    PubMed  CAS  Google Scholar 

  74. Fukumoto H, Deng A, Irizarry MC et al (2002) Induction of the cholesterol transporter ABCA1 in CNS cells by LXR agonists increases secreted Aβ levels. J Biol Chem 277:48508–48513. doi:10.1074/jbc.M209085200

    PubMed  CAS  Google Scholar 

  75. Hirsch-Reinshagen V, Chan JY, Wilkinson A et al (2007) Physiologically regulated ABCA1 does not reduce amyloid burden or beta-amyloid levels in vivo. J Lipid Res 48:914–923. doi:10.1194/jlr.M600543-JLR200

    PubMed  CAS  Google Scholar 

  76. Wahrle SE, Jiang H, Parsadanian M et al (2008) Overexpression of ABCA1 in the PDAPP mouse model of Alzheimer’s disease markedly reduces amyloid deposition. J Clin Invest 118:671–682

    PubMed  CAS  Google Scholar 

  77. Schmitz G, Langmann T, Heimerl S (2001) Role of ABCG1 and other ABCG family members in lipid metabolism. J Lipid Res 42:1513–1520

    PubMed  CAS  Google Scholar 

  78. Cavelier C, Lorenzi I, Rohrer L et al (2006) Lipid efflux by the ATP-binding cassette transporters ABCA1 and ABCG1. Biochim Biophys Acta 1761:655–666

    PubMed  CAS  Google Scholar 

  79. Vaughan AM, Oram JF (2005) ABCG1 redistributes cell cholesterol to domains removable by HDL but not by lipid-depleted apolipoproteins. J Biol Chem 280:30150–30157. doi:10.1074/jbc.M505368200

    PubMed  CAS  Google Scholar 

  80. Wang N, Ranalletta M, Matsuura F et al (2006) LXR-induced redistribution of ABCG1 to plasma membrane in macrophages enhances cholesterol mass efflux to HDL. Arterioscler Thromb Vasc Biol 26:1310–1316. doi:10.1161/01.ATV.0000218998.75963.02

    PubMed  CAS  Google Scholar 

  81. Kobayashi A, Takanezawa Y, Hirata T et al (2006) Efflux of sphingomyelin, cholesterol, and phosphatidylcholine by ABCG1. J Lipid Res 47:1791–1802. doi:10.1194/jlr.M500546-JLR200

    PubMed  CAS  Google Scholar 

  82. Terasaka N, Wang N, Yvan-Charvet L et al (2007) High-density lipoprotein protects macrophages from oxidized low-density lipoprotein-induced apoptosis by promoting efflux of 7-ketocholesterol via ABCG1. Proc Natl Acad Sci USA 104:15093–15098. doi:10.1073/pnas.0704602104

    PubMed  CAS  Google Scholar 

  83. Gelissen IC, Harris M, Rye K-A et al (2006) ABCA1 and ABCG1 synergize to mediate cholesterol export to apoA-1. Arterioscler Thromb Vasc Biol 26:534–540. doi:10.1161/01.ATV.0000200082.58536.e1

    PubMed  CAS  Google Scholar 

  84. 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. doi:10.1194/jlr.M600218-JLR200

    PubMed  CAS  Google Scholar 

  85. Kennedy MA, Barrera GC, Nakamura K et al (2005) ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. Cell Metab 1:121–131. doi:10.1016/j.cmet.2005.01.002

    PubMed  CAS  Google Scholar 

  86. Baldán A, Tarr P, Vales CS et al (2006) Deletion of the transmembrane transporter ABCG1 results in progressive pulmonary lipidosis. J Biol Chem 281:29401–29410. doi:10.1074/jbc.M606597200

    PubMed  Google Scholar 

  87. Out R, Hoekstra M, Meurs I et al (2007) Total body ABCG1 expression protects against early atherosclerotic lesion development in mice. Arterioscler Thromb Vasc Biol 27:594–599. doi:10.1161/01.ATV.0000257136.24308.0c

    PubMed  CAS  Google Scholar 

  88. Tansley GH, Burgess BL, Bryan MT et al (2007) The cholesterol transporter ABCG1 modulates the subcellular distribution and proteolytic processing of β-amyloid precursor protein. J Lipid Res 48:1022–1034. doi:10.1194/jlr.M600542-JLR200

    PubMed  CAS  Google Scholar 

  89. Wang N, Yvan-Charvet L, Lutjohann D et al (2007) ATP-binding cassette transporters G1 and G4 mediate cholesterol and desmosterol efflux to HDL and regulate sterol accumulation in the brain. FASEB J 22:1073–1082. doi:10.1096/fj.07-9944com

    PubMed  Google Scholar 

  90. Tarr PT, Edwards PA (2007) ABCG1 and ABCG4 are co-expressed in neurons and astrocytes of the CNS and regulate cholesterol homeostasis through SREBP-2. J Lipid Res 49:169–182. doi:10.1194/jlr.M700364-JLR200

    PubMed  Google Scholar 

  91. Karten B, Campenot RB, Vance D et al (2006) Expression of ABCG1, but not ABCA1, correlates with cholesterol release by cerebellar astroglia. J Biol Chem 281:4049–4057. doi:10.1074/jbc.M508915200

    PubMed  CAS  Google Scholar 

  92. Kim WS, Rahmanto AS, Kamili A et al (2006) Role of ABCG1 and ABCA1 in regulation of neuronal cholesterol efflux to apolipoprotein-E discs and suppression of amyloid-β peptide generation. J Biol Chem 282:2851–2861. doi:10.1074/jbc.M607831200

    PubMed  Google Scholar 

  93. Burgess BL, Parkinson PF, Bryan MT et al (2008) ABCG1 influcences brain cholesterol synthesis but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo. J Lipid Res 49:1254–1267. doi:10.1194/jlr.M700481-JLR200

    PubMed  CAS  Google Scholar 

  94. Beaven SW, Tontonoz P (2006) Nuclear receptors in lipid metabolism: targeting the heart of dyslipidemia. Annu Rev Med 57:313–329. doi:10.1146/annurev.med.57.121304.131428

    PubMed  CAS  Google Scholar 

  95. Kalaany NY, Mangelsdorf DJ (2006) LXRS and FXR: the yin and yang of cholesterol and fat metabolism. Annu Rev Physiol 68:159–191. doi:10.1146/annurev.physiol.68.033104.152158

    PubMed  CAS  Google Scholar 

  96. Willy JP, Umesono K, Ong ES et al (1995) LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev 9:1033–1045. doi:10.1101/gad.9.9.1033

    PubMed  CAS  Google Scholar 

  97. Claudel T, Leibowitz MD, Fievet C et al (2001) Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor. Proc Natl Acad Sci USA 98:2610–2615. doi:10.1073/pnas.041609298

    PubMed  CAS  Google Scholar 

  98. Repa JJ, Berge KE, Pomajzl C et al (2002) Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors α and β. J Biol Chem 277:18793–18800. doi:10.1074/jbc.M109927200

    PubMed  CAS  Google Scholar 

  99. Wang N, Lan D, Chen W et al (2004) ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins. Proc Natl Acad Sci USA 101:9774–9779. doi:10.1073/pnas.0403506101

    PubMed  CAS  Google Scholar 

  100. Wang N, Silver DL, Theile C et al (2001) ATP-binding cassette transporter A1 (ABCA1) functions as a cholesterol efflux regulatory protein. J Biol Chem 276:23742–23747. doi:10.1074/jbc.M102348200

    PubMed  CAS  Google Scholar 

  101. Zelcer N, Tontonoz P (2006) Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest 116:607–614. doi:10.1172/JCI27883

    PubMed  CAS  Google Scholar 

  102. Koldamova RP, Lefterov IM, Staufenbiel M et al (2005) The liver X receptor ligand TO901317 decreases amyloid β production in vitro and in a mouse model of Alzheimer’s disease. J Biol Chem 280:4079–4088. doi:10.1074/jbc.M411420200

    PubMed  CAS  Google Scholar 

  103. Riddell DR, Zhou H, Comery TA et al (2007) The LXR agonist TO901317 selectively lowers hippocampal Aβ42 and improves memory in the Tg2576 mouse model of Alzheimer’s disease. Mol Cell Neurosci 34:621–628. doi:10.1016/j.mcn.2007.01.011

    PubMed  CAS  Google Scholar 

  104. Zelcer N, Khanlou N, Clare R et al (2007) Attenuation of neuroinflammation and Alzheimer’s disease pathology by liver X receptors. Proc Natl Acad Sci USA 104:10601–10606. doi:10.1073/pnas.0701096104

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of British Columbia, 980 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada

    Veronica Hirsch-Reinshagen, Braydon L. Burgess & Cheryl L. Wellington

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  1. Veronica Hirsch-Reinshagen
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  2. Braydon L. Burgess
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  3. Cheryl L. Wellington
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Correspondence to Cheryl L. Wellington.

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Hirsch-Reinshagen, V., Burgess, B.L. & Wellington, C.L. Why lipids are important for Alzheimer disease?. Mol Cell Biochem 326, 121–129 (2009). https://doi.org/10.1007/s11010-008-0012-2

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  • DOI: https://doi.org/10.1007/s11010-008-0012-2

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