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Cholesterol
Volume 2012 (2012), Article ID 292598, 19 pages
http://dx.doi.org/10.1155/2012/292598
Review Article

Cholesterol: Its Regulation and Role in Central Nervous System Disorders

1Institut für Laboratoriumsmedizin, Vinzenz von Paul Kliniken gGmbH, Adlerstraβe 7, Postfach 103163, 70199 Stuttgart, Germany
2Dipartimento di Scienze Farmacologiche e Biomolecolari, Facoltà di Farmacia, Università di Milano, Via Balzaretti 9, 20133 Milano, Italy

Received 6 July 2012; Revised 3 September 2012; Accepted 10 September 2012

Academic Editor: Gloria L. Vega

Copyright © 2012 Matthias Orth and Stefano Bellosta. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. J. M. Dietschy and S. D. Turley, “Cholesterol metabolism in the brain,” Current Opinion in Lipidology, vol. 12, no. 2, pp. 105–112, 2001. View at Publisher · View at Google Scholar · View at Scopus
  2. I. Björkhem, S. Meaney, and A. M. Fogelman, “Brain cholesterol: long secret life behind a barrier,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 24, no. 5, pp. 806–815, 2004. View at Publisher · View at Google Scholar · View at Scopus
  3. Z. Korade and A. K. Kenworthy, “Lipid rafts, cholesterol, and the brain,” Neuropharmacology, vol. 55, no. 8, pp. 1265–1273, 2008. View at Publisher · View at Google Scholar · View at Scopus
  4. L. Fester, L. Zhou, A. Bütow et al., “Cholesterol-promoted synaptogenesis requires the conversion of cholesterol to estradiol in the hippocampus,” Hippocampus, vol. 19, no. 8, pp. 692–705, 2009. View at Publisher · View at Google Scholar · View at Scopus
  5. C. Goritz, D. H. Mauch, and F. W. Pfrieger, “Multiple mechanisms mediate cholesterol-induced synaptogenesis in a CNS neuron,” Molecular and Cellular Neuroscience, vol. 29, no. 2, pp. 190–201, 2005. View at Publisher · View at Google Scholar · View at Scopus
  6. E. I. Posse de Chaves, A. E. Rusinol, D. E. Vance, R. B. Campenot, and J. E. Vance, “Role of lipoproteins in the delivery of lipids to axons during axonal regeneration,” The Journal of Biological Chemistry, vol. 272, no. 49, pp. 30766–30773, 1997. View at Publisher · View at Google Scholar · View at Scopus
  7. A. R. Koudinov and N. V. Koudinova, “Cholesterol homeostasis failure as a unifying cause of synaptic degeneration,” Journal of the Neurological Sciences, vol. 229-230, pp. 233–240, 2005. View at Publisher · View at Google Scholar · View at Scopus
  8. J. Herz and H. H. Bock, “Lipoprotein receptors in the nervous system,” Annual Review of Biochemistry, vol. 71, pp. 405–434, 2002. View at Publisher · View at Google Scholar · View at Scopus
  9. A. E. DeBarber, Y. Eroglu, L. S. Merkens, et al., “Smith-Lemli-Opitz syndrome,” Expert Reviews in Molecular Medicine, vol. 13, p. e24, 2011.
  10. M. Madra and S. L. Sturley, “Niemann-Pick type C pathogenesis and treatment: from statins to sugars,” Clinical Lipidology, vol. 5, no. 3, pp. 387–395, 2010. View at Publisher · View at Google Scholar · View at Scopus
  11. R. C. Block, E. R. Dorsey, C. A. Beck, J. . Brenna, and I. Shoulson, “Altered cholesterol and fatty acid metabolism in Huntington disease,” Journal of Clinical Lipidology, vol. 4, no. 1, pp. 17–23, 2010. View at Publisher · View at Google Scholar · View at Scopus
  12. G. Di Paolo and T. W. Kim, “Linking lipids to Alzheimer's disease: Cholesterol and beyond,” Nature Reviews Neuroscience, vol. 12, no. 5, pp. 284–296, 2011. View at Publisher · View at Google Scholar · View at Scopus
  13. J. Herz, “Apolipoprotein E receptors in the nervous system,” Current Opinion in Lipidology, vol. 20, no. 3, pp. 190–196, 2009.
  14. R. E. Pitas, J. K. Boyles, S. H. Lee, D. Hui, and K. H. Weisgraber, “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,” The Journal of Biological Chemistry, vol. 262, no. 29, pp. 14352–14360, 1987. View at Scopus
  15. M. S. Brown and J. L. Goldstein, “Lipoprotein receptors in the liver. Control signals for plasma cholesterol traffic,” Journal of Clinical Investigation, vol. 72, no. 3, pp. 743–747, 1983. View at Scopus
  16. J. P. Couerbe, “Du cerveau, considéré sous le point du vue chimique et physiologique,” Annales De Chimie Ed De Physique, vol. 56, pp. 160–193, 1834.
  17. H. R. Waterham, “Defects of cholesterol biosynthesis,” FEBS Letters, vol. 580, no. 23, pp. 5442–5449, 2006. View at Publisher · View at Google Scholar · View at Scopus
  18. S. Bellosta, N. Ferri, L. Arnaboldi, F. Bernini, R. Paoletti, and A. Corsini, “Pleiotropic effects of statins in atherosclerosis and diabetes,” Diabetes Care, vol. 23, supplement 2, pp. B72–B78, 2000. View at Scopus
  19. S. H. Bae, J. N. Lee, B. U. Fitzky, et al., “Cholesterol biosynthesis from lanosterol. Molecular cloning, tissue distribution, expression, chromosomal localization, and regulation of rat 7-dehydrocholesterol reductase, a Smith-Lemli-Opitz syndrome-related protein,” The Journal of Biological Chemistry, vol. 274, no. 21, pp. 14624–14631, 1999. View at Scopus
  20. J. L. Gaylor, “Membrane-bound enzymes of cholesterol synthesis from lanosterol,” Biochemical and Biophysical Research Communications, vol. 292, no. 5, pp. 1139–1146, 2002. View at Publisher · View at Google Scholar · View at Scopus
  21. J. L. Goldstein and M. S. Brown, “Regulation of the mevalonate pathway,” Nature, vol. 343, no. 6257, pp. 425–430, 1990. View at Publisher · View at Google Scholar · View at Scopus
  22. G. J. Snipes and U. Suter, “Cholesterol and myelin,” Sub-Cellular Biochemistry, vol. 28, pp. 173–204, 1997. View at Scopus
  23. P. Morell and H. Jurevics, “Origin of cholesterol in myelin,” Neurochemical Research, vol. 21, no. 4, pp. 463–470, 1996. View at Publisher · View at Google Scholar · View at Scopus
  24. M. Martin, C. G. Dotti, and M. D. Ledesma, “Brain cholesterol in normal and pathological aging,” Biochimica et Biophysica Acta, vol. 1801, no. 8, pp. 934–944, 2010. View at Publisher · View at Google Scholar · View at Scopus
  25. M. Andersson, P. G. Elmberger, C. Edlund, K. Kristensson, and G. Dallner, “Rates of cholesterol, ubiquinone, dolichol and dolichyl-P biosynthesis in rat brain slices,” FEBS Letters, vol. 269, no. 1, pp. 15–18, 1990. View at Publisher · View at Google Scholar · View at Scopus
  26. I. Björkhem, M. Heverin, V. Leoni, S. Meaney, and U. Diczfalusy, “Oxysterols and Alzheimer's disease,” Acta Neurologica Scandinavica, vol. 114, no. 185, pp. 43–49, 2006. View at Publisher · View at Google Scholar · View at Scopus
  27. J. M. Dietschy and S. D. Turley, “Cholesterol metabolism in the central nervous system during early development and in the mature animal,” Journal of Lipid Research, vol. 45, no. 8, pp. 1375–1397, 2004. View at Publisher · View at Google Scholar · View at Scopus
  28. H. Waelsch, W. Sperry, and V. A. Stoyanoff, “A study of the synthesis and deposition of lipids in brain and other tissues with deuterium as an indicator,” The Journal of Biological Chemistry, vol. 135, pp. 291–296, 1940.
  29. K. Bloch, B. N. Berg, and D. Rittenberg, “The biological conversion of cholesterol to cholic acid,” The Journal of Biological Chemistry, vol. 149, pp. 511–517, 1943.
  30. H. Jurevics and P. Morell, “Cholesterol for synthesis of myelin is made locally, not imported into brain,” Journal of Neurochemistry, vol. 64, no. 2, pp. 895–901, 1995. View at Scopus
  31. S. D. Turley, D. K. Burns, C. R. Rosenfeld, and J. M. Dietschy, “Brain does not utilize low density lipoprotein-cholesterol during fetal and neonatal development in the sheep,” Journal of Lipid Research, vol. 37, no. 9, pp. 1953–1961, 1996. View at Scopus
  32. J. M. Dietschy and S. D. Turley, “Control of cholesterol turnover in the mouse,” The Journal of Biological Chemistry, vol. 277, no. 6, pp. 3801–3804, 2002. View at Publisher · View at Google Scholar · View at Scopus
  33. T. Vanmierlo, O. Weingärtner, S. Van der Pol, et al., “Dietary intake of plant sterols stably increases plant sterol levels in the murine brain,” The Journal of Lipid Research, vol. 53, no. 4, pp. 726–735, 2012.
  34. A. V. Chobanian and W. Hollander, “Body cholesterol metabolism in man. I. The equilibration of serum and tissue cholesterol,” The Journal of clinical investigation, vol. 41, pp. 1732–1737, 1962. View at Scopus
  35. D. Lütjohann, M. Stroick, T. Bertsch et al., “High doses of simvastatin, pravastatin, and cholesterol reduce brain cholesterol synthesis in guinea pigs,” Steroids, vol. 69, no. 6, pp. 431–438, 2004. View at Publisher · View at Google Scholar · View at Scopus
  36. S. Meaney, D. Lütjohann, U. Diczfalusy, and I. Björkhem, “Formation of oxysterols from different pools of cholesterol as studied by stable isotope technique: cerebral origin of most circulating 24S-hydroxycholesterol in rats, but not in mice,” Biochimica et Biophysica Acta, vol. 1486, no. 2-3, pp. 293–298, 2000. View at Publisher · View at Google Scholar · View at Scopus
  37. J. Herz and R. V. Farese Jr., “The LDL receptor gene family, apolipoprotein B and cholesterol in embryonic development,” Journal of Nutrition, vol. 129, supplement 2S, 1999. View at Scopus
  38. H. A. Jurevics, F. Z. Kidwai, and P. Morell, “Sources of cholesterol during development of the rat fetus and fetal organs,” Journal of Lipid Research, vol. 38, no. 4, pp. 723–733, 1997. View at Scopus
  39. E. D. Muse, H. Jurevics, A. D. Toews, G. K. Matsushima, and P. Morell, “Parameters related to lipid metabolism as markers of myelination in mouse brain,” Journal of Neurochemistry, vol. 76, no. 1, pp. 77–86, 2001. View at Publisher · View at Google Scholar · View at Scopus
  40. G. Saher, B. Brügger, C. Lappe-Siefke et al., “High cholesterol level is essential for myelin membrane growth,” Nature Neuroscience, vol. 8, no. 4, pp. 468–475, 2005. View at Publisher · View at Google Scholar · View at Scopus
  41. M. Ko, K. Zou, H. Minagawa et al., “Cholesterol-mediated neurite outgrowth is differently regulated between cortical and hippocampal neurons,” The Journal of Biological Chemistry, vol. 280, no. 52, pp. 42759–42765, 2005. View at Publisher · View at Google Scholar · View at Scopus
  42. A. M. Pooler, S. C. Xi, and R. J. Wurtman, “The 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitor pravastatin enhances neurite outgrowth in hippocampal neurons,” Journal of Neurochemistry, vol. 97, no. 3, pp. 716–723, 2006. View at Publisher · View at Google Scholar · View at Scopus
  43. M. Saito, E. P. Benson, M. Saito, and A. Rosenberg, “Metabolism of cholesterol and triacylglycerol in cultured chick neuronal cells, glial cells, and fibroblasts: accumulation of esterified cholesterol in serum-free culture,” Journal of Neuroscience Research, vol. 18, no. 2, pp. 319–325, 1987. View at Scopus
  44. S. Suzuki, K. Kiyosue, S. Hazama et al., “Brain-derived neurotrophic factor regulates cholesterol metabolism for synapse development,” Journal of Neuroscience, vol. 27, no. 24, pp. 6417–6427, 2007. View at Publisher · View at Google Scholar · View at Scopus
  45. U. Fünfschilling, G. Saher, L. Xiao, W. Möbius, and K. A. Nave, “Survival of adult neurons lacking cholesterol synthesis in vivo,” BMC Neuroscience, vol. 8, p. 1, 2007. View at Publisher · View at Google Scholar · View at Scopus
  46. F. W. Pfrieger, “Outsourcing in the brain: do neurons depend on cholesterol delivery by astrocytes?” BioEssays, vol. 25, no. 1, pp. 72–78, 2003. View at Publisher · View at Google Scholar · View at Scopus
  47. Z. Korade, Z. Mi, C. Portugal, and N. F. Schor, “Expression and p75 neurotrophin receptor dependence of cholesterol synthetic enzymes in adult mouse brain,” Neurobiology of Aging, vol. 28, no. 10, pp. 1522–1531, 2007. View at Publisher · View at Google Scholar · View at Scopus
  48. W. Y. Ong, J. H. Kim, X. He, P. Chen, A. A. Farooqui, and A. M. Jenner, “Changes in brain cholesterol metabolome after excitotoxicity,” Molecular Neurobiology, vol. 41, no. 2-3, pp. 299–313, 2010. View at Publisher · View at Google Scholar · View at Scopus
  49. Y. Zhang, E. L. Appelkvist, K. Kristensson, and G. Dallner, “The lipid compositions of different regions of rat brain during development and aging,” Neurobiology of Aging, vol. 17, no. 6, pp. 869–875, 1996. View at Publisher · View at Google Scholar · View at Scopus
  50. G. Quan, C. Xie, J. M. Dietschy, and S. D. Turley, “Ontogenesis and regulation of cholesterol metabolism in the central nervous system of the mouse,” Developmental Brain Research, vol. 146, no. 1-2, pp. 87–98, 2003. View at Publisher · View at Google Scholar · View at Scopus
  51. T. Numakawa, S. Suzuki, E. Kumamaru, N. Adachi, M. Richards, and H. Kunugi, “BDNF function and intracellular signaling in neurons,” Histology and Histopathology, vol. 25, no. 2, pp. 237–258, 2010. View at Scopus
  52. H. Yu and S. B. Patel, “Recent insights into the Smith-Lemli-Opitz syndrome,” Clinical Genetics, vol. 68, no. 5, pp. 383–391, 2005. View at Publisher · View at Google Scholar · View at Scopus
  53. P. E. Jira, H. R. Waterham, R. J. A. Wanders, J. A. M. Smeitink, R. C. A. Sengers, and R. A. Wevers, “Smith-Lemli-Opitz syndrome and the DHCR7 gene,” Annals of Human Genetics, vol. 67, part 3, pp. 269–280, 2003. View at Publisher · View at Google Scholar · View at Scopus
  54. B. U. Fitzky, F. F. Moebius, H. Asaoka et al., “7-Dehydrocholesterol-dependent proteolysis of HMG-CoA reductase suppresses sterol biosynthesis in a mouse model of Smith-Lemli-Opitz/RSH syndrome,” Journal of Clinical Investigation, vol. 108, no. 6, pp. 905–915, 2001. View at Publisher · View at Google Scholar · View at Scopus
  55. X. Xu, R. Bittman, G. Duportail, D. Heissler, C. Vilcheze, and E. London, “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,” The Journal of Biological Chemistry, vol. 276, no. 36, pp. 33540–33546, 2001. View at Publisher · View at Google Scholar · View at Scopus
  56. S. Vainio, M. Jansen, M. Koivusalo et al., “Significance of sterol structural specificity: desmosterol cannot replace cholesterol in lipid rafts,” The Journal of Biological Chemistry, vol. 281, no. 1, pp. 348–355, 2006. View at Publisher · View at Google Scholar · View at Scopus
  57. S. Ollila, M. T. Hyvönen, and I. Vattulainen, “Polyunsaturation in lipid membranes: dynamic properties and lateral pressure profiles,” Journal of Physical Chemistry B, vol. 111, no. 12, pp. 3139–3150, 2007. View at Publisher · View at Google Scholar · View at Scopus
  58. P. Singh, Y. D. Paila, and A. Chattopadhyay, “Differential effects of cholesterol and 7-dehydrocholesterol on the ligand binding activity of the hippocampal serotonin1A receptor: implications in SLOS,” Biochemical and Biophysical Research Communications, vol. 358, no. 2, pp. 495–499, 2007. View at Publisher · View at Google Scholar · View at Scopus
  59. V. Leoni, C. Mariotti, L. Nanetti et al., “Whole body cholesterol metabolism is impaired in Huntington's disease,” Neuroscience Letters, vol. 494, no. 3, pp. 245–249, 2011. View at Publisher · View at Google Scholar · View at Scopus
  60. S. Sipione, D. Rigamonti, M. Valenza et al., “Early transcriptional profiles in huntingtin-induced striatal cells by microarray analyses,” Human Molecular Genetics, vol. 11, no. 17, pp. 1953–1965, 2002. View at Scopus
  61. M. Valenza, J. B. Carroll, V. Leoni et al., “Cholesterol biosynthesis pathway is disturbed in YAC128 mice and is modulated by huntingtin mutation,” Human Molecular Genetics, vol. 16, no. 18, pp. 2187–2198, 2007. View at Publisher · View at Google Scholar · View at Scopus
  62. F. M. Harris, I. Tesseur, W. J. Brecht et al., “Astroglial regulation of apolipoprotein E expression in neuronal cells: implications for Alzheimer's disease,” The Journal of Biological Chemistry, vol. 279, no. 5, pp. 3862–3868, 2004. View at Publisher · View at Google Scholar · View at Scopus
  63. Q. Xu, A. Bernardo, D. Walker, T. Kanegawa, R. W. Mahley, and Y. Huang, “Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus,” Journal of Neuroscience, vol. 26, no. 19, pp. 4985–4994, 2006. View at Publisher · View at Google Scholar · View at Scopus
  64. I. Björkhem, D. Lütjohann, U. Diczfalusy, L. Ståhle, G. Ahlborg, and J. Wahren, “Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation,” Journal of Lipid Research, vol. 39, no. 8, pp. 1594–1600, 1998. View at Scopus
  65. M. Heverin, S. Meaney, D. Lütjohann, U. Diczfalusy, J. Wahren, and I. Björkhem, “Crossing the barrier: net flux of 27-hydroxycholesterol into the human brain,” Journal of Lipid Research, vol. 46, no. 5, pp. 1047–1052, 2005. View at Publisher · View at Google Scholar · View at Scopus
  66. S. Meaney, K. Bodin, U. Diczfalusy, and I. Björkhem, “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,” Journal of Lipid Research, vol. 43, no. 12, pp. 2130–2135, 2002. View at Publisher · View at Google Scholar · View at Scopus
  67. D. Lütjohann, O. Breuer, G. Ahlborg et al., “Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 18, pp. 9799–9804, 1996. View at Publisher · View at Google Scholar · View at Scopus
  68. I. Björkhem, A. Cedazo-Minguez, V. Leoni, and S. Meaney, “Oxysterols and neurodegenerative diseases,” Molecular Aspects of Medicine, vol. 30, no. 3, pp. 171–179, 2009. View at Publisher · View at Google Scholar · View at Scopus
  69. I. Björkhem and U. Diczfalusy, “Oxysterols: friends, foes, or just fellow passengers?” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 22, no. 5, pp. 734–742, 2002. View at Publisher · View at Google Scholar · View at Scopus
  70. H. J. Senn, M. Orth, E. Fitzke, W. Koster, H. Wieland, and W. Gerok, “Human serum gangliosides in hypercholesterolemia, before and after extracorporeal elimination of LDL,” Atherosclerosis, vol. 94, no. 2-3, pp. 109–117, 1992. View at Publisher · View at Google Scholar · View at Scopus
  71. H. J. Senn, M. Orth, E. Fitzke, H. Wieland, and W. Gerok, “Ganglioside in normal human serum. Concentration, pattern and transport by lipoproteins,” European Journal of Biochemistry, vol. 181, no. 3, pp. 657–662, 1989. View at Scopus
  72. V. Leoni, T. Masterman, P. Patel, S. Meaney, U. Diczfalusy, and I. Björkhem, “Side chain oxidized oxysterols in cerebrospinal fluid and the integrity of blood-brain and blood-cerebrospinal fluid barriers,” Journal of Lipid Research, vol. 44, no. 4, pp. 793–799, 2003. View at Publisher · View at Google Scholar · View at Scopus
  73. R. Lathe, “Steroid and sterol 7-hydroxylation: ancient pathways,” Steroids, vol. 67, no. 12, pp. 967–977, 2002. View at Publisher · View at Google Scholar · View at Scopus
  74. C. Xie, D. K. Burns, S. D. Turley, and J. M. Dietschy, “Cholesterol is sequestered in the brains of mice with Niemann-Pick Type C disease but turnover is increased,” Journal of Neuropathology and Experimental Neurology, vol. 59, no. 12, pp. 1106–1117, 2000. View at Scopus
  75. J. D. Wilson, “The measurement of the exchangeable pools of cholesterol in the baboon,” Journal of Clinical Investigation, vol. 49, no. 4, pp. 655–665, 1970. View at Scopus
  76. E. G. Lund, J. M. Guileyardo, and D. W. Russell, “cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 13, pp. 7238–7243, 1999. View at Publisher · View at Google Scholar · View at Scopus
  77. L. Bretillon, U. Diczfalusy, I. Björkhem et al., “Cholesterol-24S-hydroxylase (CYP46A1) is specifically expressed in neurons of the neural retina,” Current Eye Research, vol. 32, no. 4, pp. 361–366, 2007. View at Publisher · View at Google Scholar · View at Scopus
  78. E. G. Lund, C. Xie, T. Kotti, S. D. Turley, J. M. Dietschy, and D. W. Russell, “Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover,” The Journal of Biological Chemistry, vol. 278, no. 25, pp. 22980–22988, 2003. View at Publisher · View at Google Scholar · View at Scopus
  79. B. A. Janowski, P. J. Willy, T. R. Devi, J. R. Falck, and D. J. Mangelsdorf, “An oxysterol signalling pathway mediated by the nuclear receptor LXRα,” Nature, vol. 383, no. 6602, pp. 728–731, 1996. View at Publisher · View at Google Scholar · View at Scopus
  80. J. M. Lehmann, S. A. Kliewer, L. B. Moore et al., “Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway,” The Journal of Biological Chemistry, vol. 272, no. 6, pp. 3137–3140, 1997. View at Publisher · View at Google Scholar · View at Scopus
  81. J. Brown, C. Theisler, S. Silberman et al., “Differential expression of cholesterol hydroxylases in Alzheimer's disease,” The Journal of Biological Chemistry, vol. 279, no. 33, pp. 34674–34681, 2004. View at Publisher · View at Google Scholar · View at Scopus
  82. K. D. Whitney, M. A. Watson, J. L. Collins et al., “Regulation of cholesterol homeostasis by the liver X receptors in the central nervous system,” Molecular Endocrinology, vol. 16, no. 6, pp. 1378–1385, 2002. View at Publisher · View at Google Scholar · View at Scopus
  83. I. Björkhem, “Do oxysterols control cholesterol homeostasis?” Journal of Clinical Investigation, vol. 110, no. 6, pp. 725–730, 2002. View at Publisher · View at Google Scholar · View at Scopus
  84. L. Wang, G. U. Schuster, K. Hultenby, Q. Zhang, S. Andersson, and J. Å. Gustafsson, “Liver X receptors in the central nervous system: from lipid homeostasis to neuronal degeneration,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 21, pp. 13878–13883, 2002. View at Publisher · View at Google Scholar · View at Scopus
  85. M. G. Hall, L. Quignodon, and B. Desvergne, “Peroxisome proliferator-activated receptor β/δ in the brain: facts and hypothesis,” PPAR Research, vol. 2008, Article ID 780452, 10 pages, 2008. View at Publisher · View at Google Scholar · View at Scopus
  86. L. Yue and T. Mazzone, “Peroxisome proliferator-activated receptor γ stimulation of adipocyte ApoE gene transcription mediated by the liver receptor X pathway,” The Journal of Biological Chemistry, vol. 284, no. 16, pp. 10453–10461, 2009. View at Publisher · View at Google Scholar · View at Scopus
  87. A. Chawta, J. J. Repa, R. M. Evans, and D. J. Mangelsdorf, “Nuclear receptors and lipid physiology: opening the x-files,” Science, vol. 294, no. 5548, pp. 1866–1870, 2001. View at Publisher · View at Google Scholar · View at Scopus
  88. B. Dehouck, M. P. Dehouck, J. C. Fruchart, and R. Cecchelli, “Upregulation of the low density lipoprotein receptor at the blood-brain barrier: intercommunications between brain capillary endothelial cells and astrocytes,” Journal of Cell Biology, vol. 126, no. 2, pp. 465–473, 1994. View at Publisher · View at Google Scholar · View at Scopus
  89. D. Zambón, M. Quintana, P. Mata et al., “Higher incidence of mild cognitive impairment in familial hypercholesterolemia,” The American journal of medicine, vol. 123, no. 3, pp. 267–274, 2010. View at Scopus
  90. G. L. Vega, M. F. Weiner, A. M. Lipton et al., “Reduction in levels of 24S-hydroxycholesterol by statin treatment in patients with Alzheimer disease,” Archives of Neurology, vol. 60, no. 4, pp. 510–515, 2003. View at Publisher · View at Google Scholar · View at Scopus
  91. K. Fassbender, M. Stroick, T. Bertsch et al., “Effects of statins on human cerebral cholesterol metabolism and secretion of Alzheimer amyloid peptide,” Neurology, vol. 59, no. 8, pp. 1257–1258, 2002. View at Scopus
  92. M. Simons, F. Schwärzler, D. Lütjohann et al., “Treatment with simvastatin in normocholesterolemic patients with Alzheimer's disease: a 26-week randomized, placebo-controlled, double-blind trial,” Annals of Neurology, vol. 52, no. 3, pp. 346–350, 2002. View at Publisher · View at Google Scholar · View at Scopus
  93. S. Locatelli, D. Lütjohann, H. H. J. Schmidt, C. Otto, U. Beisiegel, and K. Von Bergmann, “Reduction of plasma 24S-hydroxycholesterol (cerebrosterol) levels using high-dosage simvastatin in patients with hypercholesterolemia: evidence that simvastatin affects cholesterol metabolism in the human brain,” Archives of Neurology, vol. 59, no. 2, pp. 213–216, 2002. View at Scopus
  94. T. E. Willnow, J. Hilpert, S. A. Armstrong et al., “Defective forebrain development in mice lacking gp330/megalin,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 16, pp. 8460–8464, 1996. View at Publisher · View at Google Scholar · View at Scopus
  95. E. Roessler, E. Belloni, K. Gaudenz et al., “Mutations in the human Sonic Hedgehog gene cause holoprosencephaly,” Nature genetics, vol. 14, no. 3, pp. 357–360, 1996. View at Scopus
  96. P. M. Lorusso, A. Jimeno, G. Dy, et al., “Pharmacokinetic dose-scheduling study of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors,” Clinical Cancer Research, vol. 17, no. 17, pp. 5774–5782, 2011.
  97. P. W. Ingham, Y. Nakano, and C. Seger, “Mechanisms and functions of Hedgehog signalling across the metazoa,” Nature Reviews Genetics, vol. 12, no. 6, pp. 393–406, 2011. View at Publisher · View at Google Scholar · View at Scopus
  98. J. I. Alvarez, A. Dodelet-Devillers, H. Kebir, et al., “The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence,” Science, vol. 334, no. 6063, pp. 1727–1731, 2011.
  99. J. Herz, T. E. Willnow, and R. E. Farese, “Cholesterol, hedgehog and embryogenesis,” Nature Genetics, vol. 15, no. 2, pp. 123–124, 1997. View at Publisher · View at Google Scholar · View at Scopus
  100. M. E. Baardman, J. J. Erwich, R. M. Berger, et al., “The origin of fetal sterols in second-trimester amniotic fluid: endogenous synthesis or maternal-fetal transport?” American Journal of Obstetrics and Gynecology, vol. 207, no. 3, pp. 202.e19–202.e25, 2012.
  101. L. A. Woollett, “The origins and roles of cholesterol and fatty acids in the fetus,” Current Opinion in Lipidology, vol. 12, no. 3, pp. 305–312, 2001. View at Publisher · View at Google Scholar · View at Scopus
  102. M. M. Véniant, E. Kim, S. McCormick et al., “Insights into apolipoprotein B biology from transgenic and gene-targeted mice,” Journal of Nutrition, vol. 129, supplement 2S, pp. 451S–455S, 1999. View at Scopus
  103. M. Raabe, L. M. Flynn, C. H. Zlot et al., “Knockout of the abetalipoproteinemia gene in mice: reduced lipoprotein secretion in heterozygotes and embryonic lethality in homozygotes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 15, pp. 8686–8691, 1998. View at Publisher · View at Google Scholar · View at Scopus
  104. Cholesterol Treatment Trialists C, C. Baigent, L. Blackwell, et al., “Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170, 000 participants in 26 randomised trials,” The Lancet, vol. 376, no. 9753, pp. 1670–1681, 2010.
  105. N. E. Shepardson, G. M. Shankar, and D. J. Selkoe, “Cholesterol level and statin use in Alzheimer disease: II. review of human trials and recommendations,” Archives of Neurology, vol. 68, no. 11, pp. 1385–1392, 2011.
  106. J. Z. Willey and M. S. V. Elkind, “3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors in the treatment of central nervous system diseases,” Archives of Neurology, vol. 67, no. 9, pp. 1062–1067, 2010. View at Publisher · View at Google Scholar · View at Scopus
  107. K. M. Thelen, K. M. Rentsch, U. Gutteck et al., “Brain cholesterol synthesis in mice is affected by high dose of simvastatin but not of pravastatin,” Journal of Pharmacology and Experimental Therapeutics, vol. 316, no. 3, pp. 1146–1152, 2006. View at Publisher · View at Google Scholar · View at Scopus
  108. D. L. Sparks, D. J. Connor, P. J. Browne, J. E. Lopez, and M. N. Sabbagh, “HMG-CoA reductase inhibitors (statins) in the treatment of Alzheimer's disease and why it would be ill-advise to use one that crosses the blood-brain barrier,” Journal of Nutrition, Health and Aging, vol. 6, no. 5, pp. 324–331, 2002. View at Scopus
  109. I. Serbanescu, M. A. Ryan, R. Shukla, M. A. Cortez, O. C. Snead, and S. C. Cunnane, “Lovastatin exacerbates atypical absence seizures with only minimal effects on brain sterols,” Journal of Lipid Research, vol. 45, no. 11, pp. 2038–2043, 2004. View at Publisher · View at Google Scholar · View at Scopus
  110. O. Maier, J. De Jonge, A. Nomden, D. Hoekstra, and W. Baron, “Lovastatin induces the formation of abnormal myelin-like membrane sheets in primary oligodendrocytes,” GLIA, vol. 57, no. 4, pp. 402–413, 2009. View at Publisher · View at Google Scholar · View at Scopus
  111. B. McGuinness, J. O'Hare, D. Craig, R. Bullock, R. Malouf, and P. Passmore, “Cochrane review on ‘statins for the treatment of dementia’,” International Journal of Geriatric Psychiatry. In press. View at Publisher · View at Google Scholar
  112. T. Yamamoto, C. G. Davis, and M. S. Brown, “The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA,” Cell, vol. 39, no. 1, pp. 27–38, 1984. View at Scopus
  113. W. A. Banks and M. A. Erickson, “The blood-brain barrier and immune function and dysfunction,” Neurobiology of Disease, vol. 37, no. 1, pp. 26–32, 2010. View at Publisher · View at Google Scholar · View at Scopus
  114. T. Beziaud, X. Ru Chen, N. El Shafey, et al., “Simvastatin in traumatic brain injury: effect on brain edema mechanisms,” Crit Care Med, vol. 39, no. 10, pp. 2300–2307, 2011.
  115. F. Guillot, P. Misslin, and M. Lemaire, “Comparison of fluvastatin and lovastatin blood-brain barrier transfer using in vitro and in vivo methods,” Journal of Cardiovascular Pharmacology, vol. 21, no. 2, pp. 339–346, 1993. View at Scopus
  116. A. Saheki, T. Terasaki, I. Tamai, and A. Tsuji, “In vivo and in vitro blood-brain barrier transport of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors,” Pharmaceutical Research, vol. 11, no. 2, pp. 305–311, 1994. View at Publisher · View at Google Scholar · View at Scopus
  117. K. I. Nezasa, K. Higaki, T. Matsumura et al., “Liver-specific distribution of rosuvastatin in rats: comparison with pravastatin and simvastatin,” Drug Metabolism and Disposition, vol. 30, no. 11, pp. 1158–1163, 2002. View at Publisher · View at Google Scholar · View at Scopus
  118. N. Kandiah and H. H. Feldman, “Therapeutic potential of statins in Alzheimer's disease,” Journal of the Neurological Sciences, vol. 283, no. 1-2, pp. 230–234, 2009. View at Publisher · View at Google Scholar · View at Scopus
  119. R. H. Knopp, “Drug treatment of lipid disorders,” The New England Journal of Medicine, vol. 341, no. 7, pp. 498–511, 1999. View at Publisher · View at Google Scholar · View at Scopus
  120. A. Tsuji, A. Saheki, I. Tamai, and T. Terasaki, “Transport mechanism of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors at the blood-brain barrier,” Journal of Pharmacology and Experimental Therapeutics, vol. 267, no. 3, pp. 1085–1090, 1993. View at Scopus
  121. R. M. Uranga and J. N. Keller, “Diet and age interactions with regards to cholesterol regulation and brain pathogenesis,” Current Gerontology and Geriatrics Research, vol. 2010, Article ID 219683, 14 pages, 2010. View at Publisher · View at Google Scholar · View at Scopus
  122. T. Mailman, M. Hariharan, and B. Karten, “Inhibition of neuronal cholesterol biosynthesis with lovastatin leads to impaired synaptic vesicle release even in the presence of lipoproteins or geranylgeraniol,” Journal of Neurochemistry, vol. 119, no. 5, pp. 1002–1015, 2011.
  123. M. C. Patterson, A. M. Di Bisceglie, J. J. Higgins et al., “The effect of cholesterol-lowering agents on hepatic and plasma cholesterol in Niemann-Pick disease type C,” Neurology, vol. 43, no. 1, pp. 61–64, 1993. View at Scopus
  124. B. Liu, H. Li, J. J. Repa, S. D. Turley, and J. M. Dietschy, “Genetic variations and treatments that affect the lifespan of the NPC1 mouse,” Journal of Lipid Research, vol. 49, no. 3, pp. 663–669, 2008. View at Publisher · View at Google Scholar · View at Scopus
  125. I. Bohr, “Hypercholesterolemic diet applied to rat dams protects their offspring against cognitive deficits. Simulated neonatal anoxia model,” Physiology and Behavior, vol. 82, no. 4, pp. 703–711, 2004. View at Publisher · View at Google Scholar · View at Scopus
  126. B. G. Schreurs, “The effects of cholesterol on learning and memory,” Neuroscience and Biobehavioral Reviews, vol. 34, no. 8, pp. 1366–1379, 2010. View at Publisher · View at Google Scholar · View at Scopus
  127. R. A. Whitmer, S. Sidney, J. Selby, S. Claiborne Johnston, and K. Yaffe, “Midlife cardiovascular risk factors and risk of dementia in late life,” Neurology, vol. 64, no. 2, pp. 277–281, 2005. View at Scopus
  128. K. Yaffe, E. Barrett-Connor, F. Lin, and D. Grady, “Serum lipoprotein levels, statin use, and cognitive function in older women,” Archives of Neurology, vol. 59, no. 3, pp. 378–384, 2002. View at Scopus
  129. A. Solomon, I. Kåreholt, T. Ngandu et al., “Serum cholesterol changes after midlife and late-life cognition: twenty-one-year follow-up study,” Neurology, vol. 68, no. 10, pp. 751–756, 2007. View at Publisher · View at Google Scholar · View at Scopus
  130. J. Näslund, V. Haroutunian, R. Mohs et al., “Correlation between elevated levels of amyloid β-peptide in the brain and cognitive decline,” Journal of the American Medical Association, vol. 283, no. 12, pp. 1571–1577, 2000. View at Scopus
  131. M. Kivipelto, E. L. Helkala, T. Hänninen et al., “Midlife vascular risk factors and late-life mild cognitive impairment: a population-based study,” Neurology, vol. 56, no. 12, pp. 1683–1689, 2001. View at Scopus
  132. M. M. Mielke, P. P. Zandi, M. Sjögren et al., “High total cholesterol levels in late life associated with a reduced risk of dementia,” Neurology, vol. 64, no. 10, pp. 1689–1695, 2005. View at Publisher · View at Google Scholar · View at Scopus
  133. L. A. Perry, C. B. Stigger, B. E. Ainsworth, and J. Zhang, “No association between cognitive achievements, academic performance and serum cholesterol concentrations among school-aged children,” Nutritional Neuroscience, vol. 12, no. 4, pp. 160–166, 2009. View at Publisher · View at Google Scholar · View at Scopus
  134. M. F. Muldoon, C. M. Ryan, S. M. Sereika, J. D. Flory, and S. B. Manuck, “Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults,” American Journal of Medicine, vol. 117, no. 11, pp. 823–829, 2004. View at Publisher · View at Google Scholar · View at Scopus
  135. M. F. Muldoon, S. D. Barger, C. M. Ryan et al., “Effects of lovastatin on cognitive function and psychological well-being,” American Journal of Medicine, vol. 108, no. 7, pp. 538–546, 2000. View at Publisher · View at Google Scholar · View at Scopus
  136. S. Trompet, P. Van Vliet, A. J. M. De Craen et al., “Pravastatin and cognitive function in the elderly. Results of the PROSPER study,” Journal of Neurology, vol. 257, no. 1, pp. 85–90, 2010. View at Publisher · View at Google Scholar · View at Scopus
  137. FDA and US Food and Drug Administration, “FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs 2012,” http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm?utm_source=fdaSearch&utm_medium=website&utm_term=safety%20changes%20to%20cholesterol-lowering%20statin%20drugs&utm_content=1, 2012.
  138. Z. Arvanitakis, J. A. Schneider, R. S. Wilson et al., “Statins, incident Alzheimer disease, change in cognitive function, and neuropathology,” Neurology, vol. 70, no. 19, part 2, pp. 1795–1802, 2008. View at Publisher · View at Google Scholar · View at Scopus
  139. M. D. M. Haag, A. Hofman, P. J. Koudstaal, B. H. C. Stricker, and M. M. B. Breteler, “Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 80, no. 1, pp. 13–17, 2009. View at Publisher · View at Google Scholar · View at Scopus
  140. T. D. Rea, J. C. Breitner, B. M. Psaty et al., “Statin use and the risk of incident dementia: the Cardiovascular Health Study,” Archives of Neurology, vol. 62, no. 7, pp. 1047–1051, 2005. View at Publisher · View at Google Scholar · View at Scopus
  141. W. Dong, S. Vuletic, and J. J. Albers, “Differential effects of simvastatin and pravastatin on expression of Alzheimer's disease-related genes in human astrocytes and neuronal cells,” Journal of Lipid Research, vol. 50, no. 10, pp. 2095–2102, 2009. View at Publisher · View at Google Scholar · View at Scopus
  142. S. L. Cole, A. Grudzien, I. O. Manhart, B. L. Kelly, H. Oakley, and R. Vassar, “Statins cause intracellular accumulation of amyloid precursor protein, β-secretase-cleaved fragments, and amyloid β-peptide via an isoprenoid-dependent mechanism,” The Journal of Biological Chemistry, vol. 280, no. 19, pp. 18755–18770, 2005. View at Publisher · View at Google Scholar · View at Scopus
  143. F. Lu, X. Li, A. Q. Suo, and J. W. Zhang, “Inhibition of tau hyperphosphorylation and beta amyloid production in rat brain by oral administration of atorvastatin,” Chinese Medical Journal, vol. 123, no. 14, pp. 1864–1870, 2010. View at Publisher · View at Google Scholar · View at Scopus
  144. T. Kurata, K. Miyazaki, M. Kozuki et al., “Atorvastatin and pitavastatin improve cognitive function and reduce senile plaque and phosphorylated tau in aged APP mice,” Brain Research, vol. 1371, no. C, pp. 161–170, 2011. View at Publisher · View at Google Scholar · View at Scopus
  145. A. Serrano-Pozo, G. L. Vega, D. Lütjohann et al., “Effects of simvastatin on cholesterol metabolism and Alzheimer disease biomarkers,” Alzheimer Disease and Associated Disorders, vol. 24, no. 3, pp. 220–226, 2010. View at Publisher · View at Google Scholar · View at Scopus
  146. H. H. Feldman, R. S. Doody, M. Kivipelto et al., “Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe,” Neurology, vol. 74, no. 12, pp. 956–964, 2010. View at Publisher · View at Google Scholar · View at Scopus
  147. N. Sato, M. Shinohara, H. Rakugi, et al., “Dual effects of statins on Abeta metabolism: upregulation of the degradation of APP-CTF and Abeta clearance,” Neurodegenerative Diseases, vol. 10, no. 1–4, pp. 305–308, 2012.
  148. M. S. V. Elkind, A. C. Flint, R. R. Sciacca, and R. L. Sacco, “Lipid-lowering agent use at ischemic stroke onset is associated with decreased mortality,” Neurology, vol. 65, no. 2, pp. 253–258, 2005. View at Publisher · View at Google Scholar · View at Scopus
  149. M. Blanco, F. Nombela, M. Castellanos et al., “Statin treatment withdrawal in ischemic stroke: a controlled randomized study,” Neurology, vol. 69, no. 9, pp. 904–910, 2007. View at Publisher · View at Google Scholar · View at Scopus
  150. M. S. V. Elkind, R. L. Sacco, R. B. Macarthur et al., “The Neuroprotection with Statin Therapy for Acute Recovery Trial (NeuSTART): an adaptive design phase I dose-escalation study of high-dose lovastatin in acute ischemic stroke,” International Journal of Stroke, vol. 3, no. 3, pp. 210–218, 2008. View at Publisher · View at Google Scholar · View at Scopus
  151. J. J. Cui, D. Wang, F. Gao, et al., “Effects of atorvastatin on pathological changes in brain tissue and plasma MMP-9 in rats with intracerebral hemorrhage,” Cell Biochemistry and Biophysics, vol. 62, no. 1, pp. 87–90, 2012.
  152. M. J. Ignatius, P. J. Gebicke-Harter, and J. H. P. Skene, “Expression of apolipoprotein E during nerve degeneration and regeneration,” Proceedings of the National Academy of Sciences of the United States of America, vol. 83, no. 4, pp. 1125–1129, 1986. View at Scopus
  153. R. E. Pitas, J. K. Boyles, and S. H. Lee, “Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins,” Biochimica et Biophysica Acta, vol. 917, no. 1, pp. 148–161, 1987. View at Scopus
  154. B. A. Evans, J. E. Evans, S. P. Baker et al., “Long-term statin therapy and CSF cholesterol levels: implications for alzheimer's disease,” Dementia and Geriatric Cognitive Disorders, vol. 27, no. 6, pp. 519–524, 2009. View at Publisher · View at Google Scholar · View at Scopus
  155. A. Von Eckardstein, Y. Huang, J. J. P. Kastelein et al., “Lipid-free apolipoprotein (apo) A-I is converted into alpha-migrating high density lipoproteins by lipoprotein-depleted plasma of normolipidemic donors and apo A-I-deficient patients but not of Tangier disease patients,” Atherosclerosis, vol. 138, no. 1, pp. 25–34, 1998. View at Publisher · View at Google Scholar · View at Scopus
  156. S. Bellosta, B. P. Nathan, M. Orth, L. M. Dong, R. W. Mahley, and R. E. Pitas, “Stable expression and secretion of apolipoproteins E3 and E4 in mouse neuroblastoma cells produces differential effects on neurite outgrowth,” The Journal of Biological Chemistry, vol. 270, no. 45, pp. 27063–27071, 1995. View at Publisher · View at Google Scholar · View at Scopus
  157. M. J. LaDu, S. M. Gilligan, J. R. Lukens et al., “Nascent astrocyte particles differ from lipoproteins in CSF,” Journal of Neurochemistry, vol. 70, no. 5, pp. 2070–2081, 1998. View at Scopus
  158. M. Buttini, M. Orth, S. Bellosta et al., “Expression of human apolipoprotein E3 or E4 in the brains of Apoe(-/-) mice: isoform-specific effects on neurodegeneration,” Journal of Neuroscience, vol. 19, no. 12, pp. 4867–4880, 1999. View at Scopus
  159. C. Pottier, D. Hannequin, S. Coutant, et al., “High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease,” Molecular Psychiatry, vol. 17, no. 9, pp. 875–879, 2012.
  160. M. J. Ignatius, E. M. Shooter, R. E. Pitas, and R. W. Mahley, “Lipoprotein uptake by neuronal growth cones in vitro,” Science, vol. 236, no. 4804, pp. 950–962, 1987. View at Scopus
  161. R. Spoelgen, A. Hammes, U. Anzenberger et al., “LRP2/megalin is required for patterning of the ventral telencephalon,” Development, vol. 132, no. 2, pp. 405–414, 2005. View at Publisher · View at Google Scholar · View at Scopus
  162. I. Hack, S. Hellwig, D. Junghans et al., “Divergent roles of ApoER2 and Vldlr in the migration of cortical neurons,” Development, vol. 134, no. 21, pp. 3883–3891, 2007. View at Publisher · View at Google Scholar · View at Scopus
  163. J. Herz and Y. Chen, “Reelin, lipoprotein receptors and synaptic plasticity,” Nature Reviews Neuroscience, vol. 7, no. 11, pp. 850–859, 2006. View at Publisher · View at Google Scholar · View at Scopus
  164. M. S. Durakoglugil, Y. Chen, C. L. White, E. T. Kavalali, and J. Herz, “Reelin signaling antagonizes β-amyloid at the synapse,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 37, pp. 15938–15943, 2009. View at Publisher · View at Google Scholar · View at Scopus
  165. T. Witzlack, T. Wenzeck, J. Thiery, and M. Orth, “cAMP-induced expression of ABCA1 is associated with MAP-kinase-pathway activation,” Biochemical and Biophysical Research Communications, vol. 363, no. 1, pp. 89–94, 2007. View at Publisher · View at Google Scholar · View at Scopus
  166. M. Larouche, U. Beffert, J. Herz, and R. Hawkes, “The reelin receptors Apoer2 and Vldlr coordinate the patterning of purkinje cell topography in the developing mouse cerebellum,” PLoS ONE, vol. 3, no. 2, Article ID e1653, 2008. View at Publisher · View at Google Scholar · View at Scopus
  167. Y. Zong, B. Zhang, S. Gu, et al., “Structural basis of agrin-LRP4-MuSK signaling,” Genes & Development, vol. 26, no. 3, pp. 247–258, 2012.
  168. S. Kantarci, L. Al-Gazali, R. S. Hill et al., “Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes,” Nature Genetics, vol. 39, no. 8, pp. 957–959, 2007. View at Publisher · View at Google Scholar · View at Scopus
  169. K. M. Boycott, C. Bonnemann, J. Herz et al., “Mutations in VLDLR as a cause for autosomal recessive cerebellar ataxia with mental retardation (Dysequilibrium syndrome),” Journal of Child Neurology, vol. 24, no. 10, pp. 1310–1315, 2009. View at Publisher · View at Google Scholar · View at Scopus
  170. K. M. Boycott, S. Flavelle, A. Bureau et al., “Homozygous deletion of the very low density lipoprotein receptor gene causes autosomal recessive cerebellar hypoplasia with cerebral gyral simplification,” American Journal of Human Genetics, vol. 77, no. 3, pp. 477–483, 2005. View at Publisher · View at Google Scholar · View at Scopus
  171. T. Ozcelik, N. Akarsu, E. Uz et al., “Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 11, pp. 4232–4236, 2008. View at Publisher · View at Google Scholar · View at Scopus
  172. T. J. Park and T. Curran, “Crk and Crk-like play essential overlapping roles downstream of disabled-1 in the reelin pathway,” Journal of Neuroscience, vol. 28, no. 50, pp. 13551–13562, 2008. View at Publisher · View at Google Scholar · View at Scopus
  173. G. E. Handelmann, J. K. Boyles, K. H. Weisgraber, R. W. Mahley, and R. E. Pitas, “Effects of apolipoprotein E, β-very low density lipoproteins, and cholesterol on the extension of neurites by rabbit dorsal root ganglion neurons in vitro,” Journal of Lipid Research, vol. 33, no. 11, pp. 1677–1688, 1992. View at Scopus
  174. M. Orth, W. Weng, H. Funke et al., “Effects of a frequent apolipoprotein E isoform, apoE4(Freiburg) (Leu28→Pro), on lipoproteins and the prevalence of coronary artery disease in Whites,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 19, no. 5, pp. 1306–1315, 1999. View at Scopus
  175. R. W. Mahley, “Apolipoprotein E: Cholesterol transport protein with expanding role in cell biology,” Science, vol. 240, no. 4852, pp. 622–630, 1988. View at Scopus
  176. D. K. Lahiri, “Apolipoprotein E as a target for developing new therapeutics for Alzheimer's disease based on studies from protein, RNA, and regulatory region of the gene,” Journal of Molecular Neuroscience, vol. 23, no. 3, pp. 225–233, 2004. View at Scopus
  177. M. F. Linton, R. Gish, S. T. Hubl et al., “Phenotypes of apolipoprotein B and apolipoprotein E after liver transplantation,” Journal of Clinical Investigation, vol. 88, no. 1, pp. 270–281, 1991. View at Scopus
  178. R. W. Mahley, K. H. Weisgraber, and Y. Huang, “Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 15, pp. 5644–5651, 2006. View at Publisher · View at Google Scholar · View at Scopus
  179. X. Pu-Ting, J. R. Gilbert, Q. Hui-Ling et al., “Specific regional transcription of apolipoprotein E in human brain neurons,” American Journal of Pathology, vol. 154, no. 2, pp. 601–611, 1999. View at Scopus
  180. S. E. Wahrle, H. Jiang, M. Parsadanian et al., “ABCA1 is required for normal central nervous system apoE levels and for lipidation of astrocyte-secreted apoE,” The Journal of Biological Chemistry, vol. 279, no. 39, pp. 40987–40993, 2004. View at Publisher · View at Google Scholar · View at Scopus
  181. V. Hirsch-Reinshagen, L. F. Maia, B. L. Burgess et al., “The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease,” The Journal of Biological Chemistry, vol. 280, no. 52, pp. 43243–43256, 2005. View at Publisher · View at Google Scholar · View at Scopus
  182. Q. Liu, C. V. Zerbinatti, J. Zhang et al., “Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1,” Neuron, vol. 56, no. 1, pp. 66–78, 2007. View at Publisher · View at Google Scholar · View at Scopus
  183. R. Anderson, J. C. Barnes, T. V. P. Bliss et al., “Behavioural, physiological and morphological analysis of a line of apolipoprotein E knockout mouse,” Neuroscience, vol. 85, no. 1, pp. 93–110, 1998. View at Publisher · View at Google Scholar · View at Scopus
  184. A. M. Fagan, B. A. Murphy, S. N. Patel et al., “Evidence for normal aging of the septo-hippocampal cholinergic system in apoE (-/-) mice but impaired clearance of axonal degeneration products following injury,” Experimental Neurology, vol. 151, no. 2, pp. 314–325, 1998. View at Publisher · View at Google Scholar · View at Scopus
  185. D. M. Holtzman, J. Herz, and G. Bu, “Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease,” Cold Spring Harb Perspect Med, vol. 2, no. 3, Article ID a006312, 2012.
  186. E. H. Corder, A. M. Saunders, W. J. Strittmatter et al., “Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families,” Science, vol. 261, no. 5123, pp. 921–923, 1993. View at Scopus
  187. W. J. Strittmatter, A. M. Saunders, D. Schmechel et al., “Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 5, pp. 1977–1981, 1993. View at Scopus
  188. D. E. Schmechel, A. M. Saunders, W. J. Strittmatter et al., “Increased amyloid β-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 20, pp. 9649–9653, 1993. View at Publisher · View at Google Scholar · View at Scopus
  189. A. Ward, S. Crean, C. J. Mercaldi, et al., “Prevalence of apolipoprotein E4 genotype and homozygotes (APOE e4/4) among patients diagnosed with Alzheimer's disease: a systematic review and meta-analysis,” Neuroepidemiology, vol. 38, no. 1, pp. 1–17, 2012.
  190. D. Blacker, J. L. Haines, L. Rodes et al., “ApoE-4 and age at onset of Alzheimer's disease: the NIMH genetics initiative,” Neurology, vol. 48, no. 1, pp. 139–147, 1997. View at Scopus
  191. W. J. Strittmatter, “Medicine. Old drug, new hope for Alzheimer's disease,” Science, vol. 335, no. 6075, pp. 1447–1448, 2012.
  192. D. M. Hatters, C. A. Peters-Libeu, and K. H. Weisgraber, “Apolipoprotein E structure: insights into function,” Trends in Biochemical Sciences, vol. 31, no. 8, pp. 445–454, 2006. View at Publisher · View at Google Scholar · View at Scopus
  193. G. Ramaswamy, Q. Xu, Y. Huang, and K. H. Weisgraber, “Effect of domain interaction on apolipoprotein E levels in mouse brain,” Journal of Neuroscience, vol. 25, no. 46, pp. 10658–10663, 2005. View at Publisher · View at Google Scholar · View at Scopus
  194. N. Zhong and K. H. Weisgraber, “Understanding the association of apolipoprotein E4 with Alzheimer disease: clues from its structure,” The Journal of Biological Chemistry, vol. 284, no. 10, pp. 6027–6031, 2009. View at Publisher · View at Google Scholar · View at Scopus
  195. A. K. Dunker, C. J. Oldfield, J. Meng et al., “The unfoldomics decade: an update on intrinsically disordered proteins,” BMC Genomics, vol. 9, supplement 2, p. S1, 2008. View at Publisher · View at Google Scholar · View at Scopus
  196. D. A. Sanan, K. H. Weisgraber, S. J. Russell et al., “Apolipoprotein E associates with β amyloid peptide of Alzheimer's disease to form novel monofibrils. Isoform ApoE4 associates more efficiently than ApoE3,” Journal of Clinical Investigation, vol. 94, no. 2, pp. 860–869, 1994. View at Scopus
  197. M. J. LaDu, M. T. Falduto, A. M. Manelli, C. A. Reardon, G. S. Getz, and D. E. Frail, “Isoform-specific binding of apolipoprotein E to β-amyloid,” The Journal of Biological Chemistry, vol. 269, no. 38, pp. 23403–23406, 1994. View at Scopus
  198. S. Aleshkov, C. R. Abraham, and V. I. Zannis, “Interaction of nascent apoe2, apoe3, and apoe4 isoforms expressed in mammalian cells with amyloid peptide β (1-40). Relevance to Alzheimer's disease,” Biochemistry, vol. 36, no. 34, pp. 10571–10580, 1997. View at Publisher · View at Google Scholar · View at Scopus
  199. Q. Jiang, C. Y. D. Lee, S. Mandrekar et al., “ApoE promotes the proteolytic degradation of Aβ,” Neuron, vol. 58, no. 5, pp. 681–693, 2008. View at Publisher · View at Google Scholar · View at Scopus
  200. R. B. DeMattos, J. R. Cirrito, M. Parsadanian et al., “ApoE and clusterin cooperatively suppress Aβ levels and deposition: evidence that ApoE regulates extracellular Aβ metabolism in vivo,” Neuron, vol. 41, no. 2, pp. 193–202, 2004. View at Publisher · View at Google Scholar · View at Scopus
  201. R. D. Bell, A. P. Sagare, A. E. Friedman et al., “Transport pathways for clearance of human Alzheimer's amyloid β-peptide and apolipoproteins E and J in the mouse central nervous system,” Journal of Cerebral Blood Flow and Metabolism, vol. 27, no. 5, pp. 909–918, 2007. View at Publisher · View at Google Scholar · View at Scopus
  202. B. V. Zlokovic, “The blood-brain barrier in health and chronic neurodegenerative disorders,” Neuron, vol. 57, no. 2, pp. 178–201, 2008. View at Publisher · View at Google Scholar · View at Scopus
  203. C. Frieden and K. Garai, “Structural differences between apoE3 and apoE4 may be useful in developing therapeutic agents for Alzheimer’s disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 23, pp. 8913–8918, 2012.
  204. C. A. Peters-Libeu, Y. Newhouse, D. M. Hatters, and K. H. Weisgraber, “Model of biologically active apolipoprotein E bound to dipalmitoylphosphatidylcholine,” The Journal of Biological Chemistry, vol. 281, no. 2, pp. 1073–1079, 2006. View at Publisher · View at Google Scholar · View at Scopus
  205. C. Wilson, M. R. Wardell, K. H. Weisgraber, R. W. Mahley, and D. A. Agard, “Three-dimensional structure of the LDL receptor-binding domain of human apolipoprotein E,” Science, vol. 252, no. 5014, pp. 1817–1822, 1991. View at Scopus
  206. A. Sivashanmugan and J. Wang, “A unified scheme for initiation and conformational adaptation of human apolipoprotein E N-terminal domain upon lipoprotein binding and for receptor binding activity,” The Journal of Biological Chemistry, vol. 284, no. 21, pp. 14657–14666, 2009. View at Publisher · View at Google Scholar · View at Scopus
  207. H. K. Chen, Z. S. Ji, S. E. Dodson et al., “Apolipoprotein E4 domain interaction mediates detrimental effects on mitochondria and is a potential therapeutic target for alzheimer disease,” The Journal of Biological Chemistry, vol. 286, no. 7, pp. 5215–5221, 2011. View at Publisher · View at Google Scholar · View at Scopus
  208. R. D. Bell, E. A. Winkler, I. Singh, et al., “Apolipoprotein E controls cerebrovascular integrity via cyclophilin A,” Nature, vol. 485, no. 7399, pp. 512–516, 2012.
  209. P. E. Cramer, J. R. Cirrito, D. W. Wesson, et al., “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models,” Science, vol. 335, no. 6075, pp. 1503–1506, 2012.
  210. M. P. Vitek, D. J. Christensen, D. Wilcock, et al., “APOE-mimetic peptides reduce behavioral deficits, plaques and tangles in Alzheimer's disease transgenics,” Neurodegenerative Diseases, vol. 10, no. 1–4, pp. 122–126, 2012.
  211. J. R. Lynch, W. Tang, H. Wang et al., “APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response,” The Journal of Biological Chemistry, vol. 278, no. 49, pp. 48529–48533, 2003. View at Publisher · View at Google Scholar · View at Scopus
  212. T. Nuutinen, T. Suuronen, A. Kauppinen, and A. Salminen, “Clusterin: a forgotten player in Alzheimer's disease,” Brain Research Reviews, vol. 61, no. 2, pp. 89–104, 2009. View at Publisher · View at Google Scholar · View at Scopus
  213. Y. Charnay, A. Imhof, P. G. Vallet et al., “Clusterin expression during fetal and postnatal CNS development in mouse,” Neuroscience, vol. 155, no. 3, pp. 714–724, 2008. View at Publisher · View at Google Scholar · View at Scopus
  214. A. Iwata, K. D. Browne, X. H. Chen, T. Yuguchi, and D. H. Smith, “Traumatic brain injury induces biphasic upregulation of ApoE and ApoJ protein in rats,” Journal of Neuroscience Research, vol. 82, no. 1, pp. 103–114, 2005. View at Publisher · View at Google Scholar · View at Scopus
  215. H. V. De Silva, J. A. K. Harmony, W. D. Stuart, C. M. Gil, and J. Robbins, “Apolipoprotein J: structure and tissue distribution,” Biochemistry, vol. 29, no. 22, pp. 5380–5389, 1990. View at Publisher · View at Google Scholar · View at Scopus
  216. R. W. Bailey, A. K. Dunker, C. J. Brown, E. C. Garner, and M. D. Griswold, “Clusterin, a binding protein with a molten globule-like region,” Biochemistry, vol. 40, no. 39, pp. 11828–11840, 2001. View at Publisher · View at Google Scholar · View at Scopus
  217. G. M. Cole and M. D. Ard, “Influence of lipoproteins on microglial degradation of Alzheimer's amyloid beta-protein,” Microscopy Research and Technique, vol. 50, no. 4, pp. 316–324, 2000.
  218. M. Shibata, S. Yamada, S. Ram Kumar et al., “Clearance of Alzheimer's amyloid-β1-40 peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier,” Journal of Clinical Investigation, vol. 106, no. 12, pp. 1489–1499, 2000. View at Scopus
  219. R. D. Bell, R. Deane, N. Chow et al., “SRF and myocardin regulate LRP-mediated amyloid-β clearance in brain vascular cells,” Nature Cell Biology, vol. 11, no. 2, pp. 143–153, 2009. View at Publisher · View at Google Scholar · View at Scopus
  220. D. Lütjohann, S. Meichsner, and H. Pettersson, “Lipids in Alzheimer’s disease and their potential for therapy,” Journal of Clinical Lipidology, vol. 7, no. 1, pp. 65–78, 2012.
  221. J. Popp, P. Lewczuk, H. Kölsch et al., “Cholesterol metabolism is associated with soluble amyloid precursor protein production in Alzheimer's disease,” Journal of Neurochemistry, vol. 123, no. 2, pp. 310–316, 2012. View at Publisher · View at Google Scholar · View at Scopus
  222. S. Ye, Y. Huang, K. Müllendorff et al., “Apolipoprotein (apo) E4 enhances amyloid β peptide production in cultured neuronal cells: ApoE structure as a potential therapeutic target,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 51, pp. 18700–18705, 2005. View at Publisher · View at Google Scholar · View at Scopus
  223. N. Marks and M. J. Berg, “BACE and γ-secretase characterization and their sorting as therapeutic targets to reduce amyloidogenesis,” Neurochemical Research, vol. 35, no. 2, pp. 181–210, 2010. View at Publisher · View at Google Scholar · View at Scopus
  224. H. S. Hoe, D. Wessner, U. Beffert, A. G. Becker, Y. Matsuoka, and G. W. Rebeck, “F-spondin interaction with the apolipoprotein E receptor ApoEr2 affects processing of amyloid precursor protein,” Molecular and Cellular Biology, vol. 25, no. 21, pp. 9259–9268, 2005. View at Publisher · View at Google Scholar · View at Scopus
  225. A. Rietveld and K. Simons, “The differential miscibility of lipids as the basis for the formation of functional membrane rafts,” Biochimica et Biophysica Acta, vol. 1376, no. 3, pp. 467–479, 1998. View at Publisher · View at Google Scholar · View at Scopus
  226. M. Koistinaho, S. Lin, X. Wu et al., “Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-β peptides,” Nature Medicine, vol. 10, no. 7, pp. 719–726, 2004. View at Publisher · View at Google Scholar · View at Scopus
  227. J. El Khoury and A. D. Luster, “Mechanisms of microglia accumulation in Alzheimer's disease: therapeutic implications,” Trends in Pharmacological Sciences, vol. 29, no. 12, pp. 626–632, 2008. View at Publisher · View at Google Scholar · View at Scopus
  228. L. M. Billings, S. Oddo, K. N. Green, J. L. McGaugh, and F. M. LaFerla, “Intraneuronal Aβ causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice,” Neuron, vol. 45, no. 5, pp. 675–688, 2005. View at Publisher · View at Google Scholar · View at Scopus
  229. K. R. Bales, T. Verina, R. C. Dodel et al., “Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition,” Nature genetics, vol. 17, no. 3, pp. 263–264, 1997. View at Scopus
  230. J. Abad-Rodriguez, M. D. Ledesma, K. Craessaerts et al., “Neuronal membrane cholesterol loss enhances amyloid peptide generation,” Journal of Cell Biology, vol. 167, no. 5, pp. 953–960, 2004. View at Publisher · View at Google Scholar · View at Scopus
  231. C. Kaether and C. Haass, “A lipid boundary separates APP and secretases and limits amyloid β-peptide generation,” Journal of Cell Biology, vol. 167, no. 5, pp. 809–812, 2004. View at Publisher · View at Google Scholar · View at Scopus
  232. M. Simons, P. Keller, B. De Strooper, K. Beyreuther, C. G. Dotti, and K. Simons, “Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neurons,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 11, pp. 6460–6464, 1998. View at Publisher · View at Google Scholar · View at Scopus
  233. R. Ehehalt, P. Keller, C. Haass, C. Thiele, and K. Simons, “Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts,” Journal of Cell Biology, vol. 160, no. 1, pp. 113–123, 2003. View at Publisher · View at Google Scholar · View at Scopus