Neurobiology of Aging
Volume 30, Issue 4 , Pages 591-599 , April 2009

ApoE4 disrupts sterol and sphingolipid metabolism in Alzheimer's but not normal brain

  • Veera Venkata Ratnam Bandaru

      Affiliations

    • Department of Neurology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, United States
    • ,
  • Juan Troncoso

      Affiliations

    • Department of Neurology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, United States
    • Department of Pathology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, United States
    • ,
  • David Wheeler

      Affiliations

    • Department of Neurology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, United States
    • ,
  • Olga Pletnikova

      Affiliations

    • Department of Pathology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, United States
    • ,
  • Jessica Wang

      Affiliations

    • Department of Neurology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, United States
    • ,
  • Kathy Conant

      Affiliations

    • Department of Neurology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, United States
    • ,
  • Norman J. Haughey

      Affiliations

    • Department of Neurology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, United States
    • Corresponding Author InformationCorresponding author. Tel.: +1 443 287 3825; fax: +1 410 955 0672.

Received 20 April 2007 ,Revised 17 July 2007 ,Accepted 25 July 2007.

References 

  1. Abad-Rodriguez J, Ledesma MD, Craessaerts K, Perga S, Medina M, Delacourte A, et al. Neuronal membrane cholesterol loss enhances amyloid peptide generation. J. Cell. Biol. 2004;167:953–960
  2. Bodovitz S, Klein WL. Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein. J. Biol. Chem. 1996;271:4436–4440
  3. Bohnet K, Pillot T, Visvikis S, Sabolovic N, Siest G. Apolipoprotein (apo) E genotype and apoE concentration determine binding of normal very low density lipoproteins to HepG2 cell surface receptors. J. Lipid Res. 1996;37:1316–1324
  4. Brann AB, Scott R, Neuberger Y, Abulafia D, Boldin S, Fainzilber M, et al. Ceramide signaling downstream of the p75 neurotrophin receptor mediates the effects of nerve growth factor on outgrowth of cultured hippocampal neurons. J. Neurosci. 1999;19:8199–8206
  5. Brown CM, Wright E, Colton CA, Sullivan PM, Laskowitz DT, Vitek MP. Apolipoprotein E isoform mediated regulation of nitric oxide release. Free Radic. Biol. Med. 2002;32:1071–1075
  6. Castiglione M, Spinsanti P, Iacovelli L, Lenti L, Martini F, Gradini R, et al. Activation of Fas receptor is required for the increased formation of the disialoganglioside GD3 in cultured cerebellar granule cells committed to apoptotic death. Neuroscience. 2004;126:889–898
  7. Colton CA, Brown CM, Czapiga M, Vitek MP. Apolipoprotein-E allele-specific regulation of nitric oxide production. Ann. N.Y. Acad. Sci. 2002;962:212–225
  8. Cordy JM, Hussain I, Dingwall C, Hooper NM, Turner AJ. Exclusively targeting beta-secretase to lipid rafts by GPI-anchor addition up-regulates beta-site processing of the amyloid precursor protein. Proc. Natl. Acad. Sci. U.S.A. 2003;100:11735–11740
  9. Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatanpaa K, et al. Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease. Proc. Natl. Acad. Sci. U.S.A. 2004;101:2070–2075
  10. Cutler RG, Haughey NJ, Tammara A, McArthur JC, Nath A, Reid R, et al. Dysregulation of sphingolipid and sterol metabolism by ApoE4 in HIV dementia. Neurology. 2004;63:626–630
  11. Dong LM, Wilson C, Wardell MR, Simmons T, Mahley RW, Weisgraber KH, et al. Human apolipoprotein E, Role of arginine 61 in mediating the lipoprotein preferences of the E3 and E4 isoforms. J. Biol. Chem. 1994;269:22358–22365
  12. Ehehalt R, Keller P, Haass C, Thiele C, Simons K. Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts. J. Cell. Biol. 2003;160:113–123
  13. Fagan AM, Bu G, Sun Y, Daugherty A, Holtzman DM. Apolipoprotein E-containing high density lipoprotein promotes neurite outgrowth and is a ligand for the low density lipoprotein receptor-related protein. J. Biol. Chem. 1996;271:30121–30125
  14. Gregg RE, Zech LA, Schaefer EJ, Stark D, Wilson D, Brewer HB. Abnormal in vivo metabolism of apolipoprotein E4 in humans. J. Clin. Invest. 1986;78:815–821
  15. Guillaume D, Bertrand P, Dea D, Davignon J, Poirier J. Apolipoprotein E and low-density lipoprotein binding and internalization in primary cultures of rat astrocytes: isoform-specific alterations. J. Neurochem. 1996;66:2410–2418
  16. Han XDMH, McKeel DW, Kelley J, Morris JC. Substantial sulfatide deficiency and ceramide elevation in very early Alzheimer's disease: potential role in disease pathogenesis. J. Neurochem. 2002;82:809–818
  17. Haughey NJ, Cutler RG, Tamara A, McArthur JC, Vargas DL, Pardo CA, et al. Involvement of perturbed sphingolipid metabolism and ceramide production in the pathogenesis of HIV dementia. Ann. Neurol. 2003;55:257–267
  18. Haughey NJ, Cutler RG, Tamara A, McArthur JC, Vargas DL, Pardo CA, et al. Perturbation of sphingolipid metabolism and ceramide production in HIV-dementia. Ann. Neurol. 2004;55:257–267
  19. Heeren J, Grewal T, Laatsch A, Becker N, Rinninger F, Rye KA, et al. Impaired recycling of apolipoprotein E4 is associated with intracellular cholesterol accumulation. J. Biol. Chem. 2004;279:55483–55492
  20. Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J. Lipid Res. 1990;31:545–548
  21. Huang Y, von Eckardstein A, Wu S, Assmann G. Effects of the apolipoprotein E polymorphism on uptake and transfer of cell-derived cholesterol in plasma. J. Clin. Invest. 1995;96:2693–2701
  22. Ignatius MJ, Shooter EM, Pitas RE, Mahley RW. Lipoprotein uptake by neuronal growth cones in vitro. Science. 1987;236:959–962
  23. Knouff C, Hinsdale ME, Mezdour H, Altenburg MK, Watanabe M, Quarfordt SH, et al. Apo E structure determines VLDL clearance and atherosclerosis risk in mice. J. Clin. Invest. 1999;103:1579–1586
  24. Kojro E, Gimpl G, Lammich S, Marz W, Fahrenholz F. Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha-secretase ADAM 10. Proc. Natl. Acad. Sci. U.S.A. 2001;98:5815–5820
  25. Lee JT, Xu J, Lee JM, Ku G, Han X, Yang DI, et al. Amyloid-beta peptide induces oligodendrocyte death by activating the neutral sphingomyelinase-ceramide pathway. J. Cell. Biol. 2004;164:123–131
  26. Lehtovirta M, Soininen H, Laakso MP, Partanen K, Helisalmi S, Mannermaa A, et al. SPECT and MRI analysis in Alzheimer's disease: relation to apolipoprotein E epsilon 4 allele. J. Neurol. Neurosurg. Psychiatry. 1996;60:644–649
  27. Levi O, Jongen-Relo AL, Feldon J, Roses AD, Michaelson DM. ApoE4 impairs hippocampal plasticity isoform-specifically and blocks the environmental stimulation of synaptogenesis and memory. Neurobiol. Dis. 2003;13:273–282
  28. Love S, Siew LK, Dawbarn D, Wilcock GK, Ben-Shlomo Y, Allen SJ. Premorbid effects of APOE on synaptic proteins in human temporal neocortex. Neurobiol. Aging. 2005;
  29. Lutjohann D, Papassotiropoulos A, Bjorkhem I, Locatelli S, Bagli M, Oehring RD, et al. Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients. J. Lipid Res. 2000;41:195–198
  30. Mauch DH, Nagler K, Schumacher S, Goritz C, Muller EC, Otto A, et al. CNS synaptogenesis promoted by glia-derived cholesterol. Science. 2001;294:1354–1357
  31. Michikawa M, Fan QW, Isobe I, Yanagisawa K. Apolipoprotein E exhibits isoform-specific promotion of lipid efflux from astrocytes and neurons in culture. J. Neurochem. 2000;74:1008–1016
  32. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, et al. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology. 1991;41:479–486
  33. Mulder M, Ravid R, Swaab DF, de Kloet ER, Haasdijk ED, Julk J, et al. Reduced levels of cholesterol, phospholipids, and fatty acids in cerebrospinal fluid of Alzheimer disease patients are not related to apolipoprotein E4. Alzheimer Dis. Assoc. Disord. 1998;12:198–203
  34. Narita M, Bu G, Holtzman DM, Schwartz AL. The low-density lipoprotein receptor-related protein, a multifunctional apolipoprotein E receptor, modulates hippocampal neurite development. J. Neurochem. 1997;68:587–595
  35. Nathan BP, Bellosta S, Sanan DA, Weisgraber KH, Mahley RW, Pitas RE. Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro. Science. 1994;264:850–852
  36. Nathan BP, Jiang Y, Wong GK, Shen F, Brewer GJ, Struble RG. Apolipoprotein E4 inhibits, and apolipoprotein E3 promotes neurite outgrowth in cultured adult mouse cortical neurons through the low-density lipoprotein receptor-related protein. Brain Res. 2002;928:96–105
  37. Papassotiropoulos A, Lutjohann D, Bagli M, Locatelli S, Jessen F, Buschfort R, et al. 24S-hydroxycholesterol in cerebrospinal fluid is elevated in early stages of dementia. J. Psychiatr. Res. 2002;36:27–32
  38. Perugini MA, Schuck P, Howlett GJ. Differences in the binding capacity of human apolipoprotein E3 and E4 to size-fractionated lipid emulsions. Eur. J. Biochem. 2002;269:5939–5949
  39. Riddell DR, Christie G, Hussain I, Dingwall C. Compartmentalization of beta-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts. Curr. Biol. 2001;11:1288–1293
  40. Sanchez-Alavez M, Tabarean IV, Behrens MM, Bartfai T. Ceramide mediates the rapid phase of febrile response to IL-1beta. Proc. Natl. Acad. Sci. U.S.A. 2006;103:2904–2908
  41. Sortino MA, Condorelli F, Vancheri C, Canonico PL. Tumor necrosis factor-alpha induces apoptosis in immortalized hypothalamic neurons: involvement of ceramide-generating pathways. Endocrinology. 1999;140:4841–4849
  42. Trommsdorff M, Gotthardt M, Hiesberger T, Shelton J, Stockinger W, Nimpf J, et al. Reeler/disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell. 1999;97:689–701
  43. Veinbergs I, Van Uden E, Mallory M, Alford M, McGiffert C, DeTeresa R, et al. Role of apolipoprotein E receptors in regulating the differential in vivo neurotrophic effects of apolipoprotein E. Exp. Neurol. 2001;170:15–26
  44. Wahrle S, Das P, Nyborg AC, McLendon C, Shoji M, Kawarabayashi T, et al. Cholesterol-dependent gamma-secretase activity in buoyant cholesterol-rich membrane microdomains. Neurobiol. Dis. 2002;9:11–23
  45. Weisgraber KH. Apolipoprotein E distribution among human plasma lipoproteins: role of the cysteine-arginine interchange at residue 112. J. Lipid Res. 1990;31:1503–1511

PII: S0197-4580(07)00299-0

doi: 10.1016/j.neurobiolaging.2007.07.024

Neurobiology of Aging
Volume 30, Issue 4 , Pages 591-599 , April 2009

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