Skip to main content

Advertisement

SpringerLink
Log in

Alzheimer’s Disease and Cholesterol: The Fat Connection

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Since the discovery of the significance of the cholesterol-carrying apolipoprotein E and cholesterolaemia as major risk factors for Alzheimer’s Disease (AD) there has been a mounting interest in the role of this lipid as a possible pathogenic agent. In this review we analyse the current evidence linking cholesterol metabolism and regulation in the CNS with the known mechanisms underlying the development of Alzheimer’s Disease. Cholesterol is known to affect amyloid-β generation and toxicity, although it must be considered that the results studies using the statin class of drugs to lower plasma cholesterol may be affected by other effects associated with these drugs. Finally, we report some of our results pointing at the interplay between neurons and astrocytes and NADPH oxidase activation as a new candidate mechanism linking cholesterol and AD pathology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Blass JP, Gibson GE (1991) The role of oxidative abnormalities in the pathophysiology of Alzheimer’s disease. Rev Neurol (Paris) 147:513–525

    CAS  Google Scholar 

  2. Canevari L, Abramov AY, Duchen MR (2004) Toxicity of amyloid beta peptide: tales of calcium, mitochondria, and oxidative stress. Neurochem Res 29:637–650

    Article  PubMed  CAS  Google Scholar 

  3. Mark RJ, Blanc EM, Mattson MP (1996) Amyloid beta-peptide and oxidative cellular injury in Alzheimer’s disease. Mol Neurobiol 12:211–224

    PubMed  CAS  Google Scholar 

  4. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923

    Article  PubMed  CAS  Google Scholar 

  5. Hofman A, Ott A, Breteler MM, Bots ML, Slooter AJ, van Hurskamp HF, van Duijn CN, Van Broeckhiven C, Grobbee DE (1997) Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer’s disease in the Rotterdam Study. Lancet 349:151–154

    Article  PubMed  CAS  Google Scholar 

  6. Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G (2000) Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol 57:1439–1443

    Article  PubMed  CAS  Google Scholar 

  7. Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA (2000) Statins and the risk of dementia. Lancet 356:1627–1631

    Article  PubMed  CAS  Google Scholar 

  8. Maxfield FR, Tabas I (2005) Role of cholesterol and lipid organization in disease. Nature 438:612–621

    Article  PubMed  CAS  Google Scholar 

  9. Simons K, Ikonen E (1997) Functional rafts in cell membranes. Nature 387:569–572

    Article  PubMed  CAS  Google Scholar 

  10. Rothberg KG, Heuser JE, Donzell WC, Ying YS, Glenney JR, Anderson RG (1992) Caveolin, a protein component of caveolae membrane coats. Cell 68:673–682

    Article  PubMed  CAS  Google Scholar 

  11. Schroeder F, Gallegos AM, Atshaves BP, Storey SM, McIntosh AL, Petrescu AD, Huang H, Starodub O, Chao H, Yang H, Frolov A, Kier AB (2001) Recent advances in membrane microdomains: rafts, caveolae, and intracellular cholesterol trafficking. Exp Biol Med (Maywood) 226:873–890

    CAS  Google Scholar 

  12. Brown MS, Goldstein JL (1986) A receptor-mediated pathway for cholesterol homeostasis. Science 232:34–47

    Article  PubMed  CAS  Google Scholar 

  13. Chobanian AV, Hollander W (1962) Body cholesterol metabolism in man. I. The equilibration of serum and tissue cholesterol. J Clin Invest 41:1732–1737

    Article  PubMed  CAS  Google Scholar 

  14. Serougne-Gautheron C, Chevallier F (1973) Time course of biosynthetic cholesterol in the adult rat brain. Biochim Biophys Acta 316:244–250

    PubMed  CAS  Google Scholar 

  15. Björkhem I, Lütjohann D, Diczfalusy U, Stahle L, Ahlborg G, Wahren J (1998) Cholesterol homeostasis in 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 

  16. Lütjohann D, Breuer O, Ahlborg G, Nennesmo I, Siden A, Diczfalusy U, Björkhem I (1996) Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation. Proc Natl Acad Sci U S A 93:9799–9804

    Article  PubMed  Google Scholar 

  17. Dietschy JM, Turley SD (2004) Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res 45:1375–1397

    Article  PubMed  CAS  Google Scholar 

  18. Saito M, Benson EP, Saito M, Rosenberg A (1987) Metabolism of cholesterol and triacylglycerol in cultured chick neuronal cells, glial cells, and fibroblasts: accumulation of esterified cholesterol in serum-free culture. J Neurosci Res 18:319–325

    Article  PubMed  CAS  Google Scholar 

  19. Beffert U, Danik M, Krzywkowski P, Ramassamy C, Berrada F, Poirier J (1998) The neurobiology of apolipoproteins and their receptors in the CNS and Alzheimer’s disease. Brain Res Rev 27:119–142

    Article  PubMed  CAS  Google Scholar 

  20. Wahrle SE, Jiang H, Parsadanian M, Legleiter J, Han X, Fryer JD, Kowalewski T, Holtzman DM (2004) ABCA1 is required for normal central nervous system apoE levels and for lipidation of astrocyte-secreted apoE. J Biol Chem 279:40987–40993

    Article  PubMed  CAS  Google Scholar 

  21. Mauch DH, Nagler K, Schumacher S, Goritz C, Muller EC, Otto A, Pfrieger FW (2001) CNS synaptogenesis promoted by glia-derived cholesterol. Science 294:1354–1357

    Article  PubMed  CAS  Google Scholar 

  22. Liang Y, Lin S, Beyer TP, Zhang Y, Wu X, Bales KR, DeMattos RB, May PC, Li SD, Jiang XC, Eacho PI, Cao G, Paul SM (2004) A liver X receptor and retinoid X receptor heterodimer mediates apolipoprotein E expression, secretion and cholesterol homeostasis in astrocytes. J Neurochem 88:623–634

    Article  PubMed  CAS  Google Scholar 

  23. Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ (1996) An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature 383:728–731

    Article  PubMed  CAS  Google Scholar 

  24. Abildayeva K, Jansen PJ, Hirsch-Reinshagen V, Bloks VW, Bakker AHF, Ramaekers FCS, de Vente J, Groen AK, Cheryl L, Kuipers F, Mulder M (2006) 24(S)-Hydroxycholesterol participates in a liver X receptor-controlled pathway in astrocytes that regulates apolipoprotein E-mediated cholesterol efflux. J Biol Chem 281:12799–12808

    Article  PubMed  CAS  Google Scholar 

  25. Sinensky M (1977) Isolation of a mammalian cell mutant resistant to 25-hydroxy cholesterol. Biochemical and Biophysical Research Communications 78:863–867

    Article  PubMed  CAS  Google Scholar 

  26. Mori T, Paris D, Town T, Rojiani AM, Sparks DL, Delledonne A, Crawford F, Abdullah LI, Humphrey JA, Dickson DW, Mullan MJ (2001) Cholesterol accumulates in senile plaques of Alzheimer disease patients and in transgenic APP(SW) mice. J Neuropathol Exp Neurol 60:778–785

    PubMed  CAS  Google Scholar 

  27. Kivipelto M, Helkala EL, Hanninen T, Laakso MP, Hallikainen M, Alhainen K, Soininen H, Tuomilehto J, Nissinen A (2001) Midlife vascular risk factors and late-life mild cognitive impairment: A population-based study. Neurology 56:1683–1689

    PubMed  CAS  Google Scholar 

  28. Pappolla MA, Bryant-Thomas TK, Herbert D, Pacheco J, Fabra GM, Manjon M, Girones X, Henry TL, Matsubara E, Zambon D, Wolozin B, Sano M, Cruz-Sanchez FF, Thal LJ, Petanceska SS, Refolo LM (2003) Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology. Neurology 61:199–205

    PubMed  CAS  Google Scholar 

  29. Whitmer RA, Sidney S, Selby J, Johnston SC, Yaffe K (2005) Midlife cardiovascular risk factors and risk of dementia in late life. Neurology 64:277–281

    PubMed  CAS  Google Scholar 

  30. Eckert GP, Wood WG, Müller WE (2001) Effects of aging and beta-amyloid on the properties of brain synaptic and mitochondrial membranes. J Neural Transm 108:1051–1064

    Article  PubMed  CAS  Google Scholar 

  31. Papassotiropoulos A, Lütjohann D, Bagli M, Locatelli S, Jessen F, Rao ML, Maier W, Björkhem I, von Bergmann K, Heun R (2000) Plasma 24S-hydroxycholesterol: a peripheral indicator of neuronal degeneration and potential state marker for Alzheimer’s disease. Neuroreport 11:1959–1962

    Article  PubMed  CAS  Google Scholar 

  32. Sparks DL, Sabbagh MN, Connor DJ, Lopez J, Launer LJ, Browne P, Wasser D, Johnson-Traver S, Lochhead J, Ziolwolski C (2005) Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch Neurol 62:753–757

    Article  PubMed  Google Scholar 

  33. Distl R, Meske V, Ohm TG (2001) Tangle-bearing neurons contain more free cholesterol than adjacent tangle-free neurons. Acta Neuropathol (Berl) 101:547–554

    CAS  Google Scholar 

  34. Thelen KM, Falkai P, Bayer TA, Lütjohann D (2006) Cholesterol synthesis rate in human hippocampus declines with aging. Neurosci Lett 403:15–19

    Article  PubMed  CAS  Google Scholar 

  35. Eckert GP, Cairns NJ, Maras A, Gattaz WF, Müller WE (2000) Cholesterol modulates the membrane-disordering effects of beta-amyloid peptides in the hippocampus: Specific changes in Alzheimer’s disease. Dementia Geriatric Cogn Disord 11:181–186

    Article  CAS  Google Scholar 

  36. Mielke MM, Zandi PP, Sjogren M, Gustafson D, Ostling S, Steen B, Skoog I (2005) High total cholesterol levels in late life associated with a reduced risk of dementia. Neurology 64:1689–1695

    Article  PubMed  CAS  Google Scholar 

  37. Li G, Shofer JB, Kukull WA, Peskind ER, Tsuang DW, Breitner JC, McCormick W, Bowen JD, Teri L, Schellenberg GD, Larson EB (2005) Serum cholesterol and risk of Alzheimer disease: a community-based cohort study. Neurology 65:1045–1050

    Article  PubMed  CAS  Google Scholar 

  38. Reitz C, Tang MX, Luchsinger J, Mayeux R (2004) Relation of plasma lipids to Alzheimer disease and vascular dementia. Arch Neurol 61:705–714

    Article  PubMed  Google Scholar 

  39. Wood WG, Igbavboa U, Eckert GP, Johnson-Anuna LN, Müller WE (2005) Is hypercholesterolemia a risk factor for Alzheimer’s disease? Mol Neurobiol 31:185–192

    Article  PubMed  CAS  Google Scholar 

  40. Papassotiropoulos A, Wollmer MA, Tsolaki M, Brunner F, Molyva D, Lütjohann D, Nitsch RM, Hock C (2005) A cluster of cholesterol-related genes confers susceptibility for Alzheimer’s disease. J Clin Psychiatry 66:940–947

    Article  PubMed  CAS  Google Scholar 

  41. Kolsch H, Lütjohann D, Ludwig M, Schulte A, Ptok U, Jessen F, von Bergmann K, Rao ML, Maier W, Heun R (2002) Polymorphism in the cholesterol 24S-hydroxylase gene is associated with Alzheimer’s disease. Mol Psychiatry 7:899–902

    Article  PubMed  CAS  Google Scholar 

  42. Katzov H, Chalmers K, Palmgren J, Andreasen N, Johansson B, Cairns NJ, Gatz M, Wilcock GK, Love S, Pedersen NL, Brookes AJ, Blennow K, Kehoe PG, Prince JA (2004) Genetic variants of ABCA1 modify Alzheimer disease risk and quantitative traits related to beta-amyloid metabolism. Hum Mutat 23:358–367

    Article  PubMed  CAS  Google Scholar 

  43. Chalmers KA, Culpan D, Kehoe PG, Wilcock GK, Hughes A, Love S (2004) APOE promoter, ACE1 and CYP46 polymorphisms and beta-amyloid in Alzheimer’s disease. Neuroreport 15:95–98

    Article  PubMed  CAS  Google Scholar 

  44. Ingelsson M, Jesneck J, Irizarry MC, Hyman BT, Rebeck GW (2004) Lack of association of the cholesterol 24-hydroxylase (CYP46) intron 2 polymorphism with Alzheimer’s disease. Neurosci Lett 367:228–231

    Article  PubMed  CAS  Google Scholar 

  45. Bogdanovic N, Bretillon L, Lund EG, Diczfalusy U, Lannfelt L, Winblad B, Russell DW, Björkhem I. (2001) On the turnover of brain cholesterol in patients with Alzheimer’s disease. Abnormal induction of the cholesterol-catabolic enzyme CYP46 in glial cells. Neuroscience Letters 314:45–48

    Article  PubMed  CAS  Google Scholar 

  46. Sparks DL, Scheff SW, Hunsaker JC III, Liu H, Landers T, Gross DR (1994) Induction of Alzheimer-like beta-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol. Exp Neurol 126:88–94

    Article  PubMed  CAS  Google Scholar 

  47. Zatta P, Zambenedetti P, Stella MP, Licastro F (2002) Astrocytosis, microgliosis, metallothionein-I-II and amyloid expression in high cholesterol-fed rabbits. J Alzheimers Dis 4:1–9

    PubMed  Google Scholar 

  48. Refolo LM, Malester B, LaFrancois J, Bryant-Thomas T, Wang R, Tint GS, Sambamurti K, Duff K, Pappolla MA (2000) Hypercholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model. Neurobiol Dis 7:321–331

    Article  PubMed  CAS  Google Scholar 

  49. Chauhan NB, Siegel GJ, Feinstein DL (2004) Effects of lovastatin and pravastatin on amyloid processing and inflammatory response in TgCRND8 brain. Neurochem Res 29:1897–1911

    Article  PubMed  CAS  Google Scholar 

  50. Fassbender K, Simons M, Bergmann C, Stroick M, Lütjohann D, Keller P, Runz H, Kuhl S, Bertsch T, von Bergmann K, Hennerici M, Beyreuther K, Hartmann T (2001) Simvastatin strongly reduces levels of Alzheimer’s disease beta -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci U S A 98:5856–5861

    Article  PubMed  CAS  Google Scholar 

  51. Simons M, Schwarzler F, Lütjohann D, von Bergmann K, Beyreuther K, Dichgans J, Wormstall H, Hartmann T, Schulz JB (2002) Treatment with simvastatin in normocholesterolemic patients with Alzheimer’s disease: A 26-week randomized, placebo-controlled, double-blind trial. Ann Neurol 52:346–350

    Article  PubMed  CAS  Google Scholar 

  52. Hoglund K, Syversen S, Lewczuk P, Wallin A, Wiltfang J, Blennow K (2005) Statin treatment and a disease-specific pattern of beta-amyloid peptides in Alzheimer’s disease. Exp Brain Res 164:205–214

    Article  PubMed  CAS  Google Scholar 

  53. Sparks DL, Petanceska S, Sabbagh M, Connor D, Soares H, Adler C, Lopez J, Ziolkowski C, Lochhead J, Browne P (2005) Cholesterol, copper and Abeta in controls, MCI, AD and the AD cholesterol-lowering treatment trial (ADCLT). Curr Alzheimer Res 2:527–539

    Article  PubMed  CAS  Google Scholar 

  54. Simons M, Keller P, De Strooper B, Beyreuther K, Dotti CG, Simons K (1998) Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci USA 95:6460–6464

    Article  PubMed  CAS  Google Scholar 

  55. Curtain CC, Ali FE, Smith DG, Bush AI, Masters CL, Barnham KJ (2003) Metal ions, pH, and cholesterol regulate the interactions of Alzheimer’s disease amyloid-beta peptide with membrane lipid. J Biol Chem 278:2977–2982

    Article  PubMed  CAS  Google Scholar 

  56. Yip CM, Elton EA, Darabie AA, Morrison MR, McLaurin J (2001) Cholesterol, a modulator of membrane-associated Abeta-fibrillogenesis and neurotoxicity. J Mol Biol 311:723–734

    Article  PubMed  CAS  Google Scholar 

  57. Riddell DR, Christie G, Hussain I, Dingwall C (2001) Compartmentalization of beta-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts. Curr Biol 11:1288–1293

    Article  PubMed  CAS  Google Scholar 

  58. Chen TY, Liu PH, Ruan CT, Chiu L, Kung FL (2006) The intracellular domain of amyloid precursor protein interacts with flotillin-1, a lipid raft protein. Biochem Biophys Res Commun 342:266–272

    Article  PubMed  CAS  Google Scholar 

  59. Wahrle S, Das P, Nyborg AC, McLendon C, Shoji M, Kawarabayashi T, Younkin LH, Younkin SG, Golde TE (2002) Cholesterol-dependent gamma-secretase activity in buoyant cholesterol-rich membrane microdomains. Neurobiol Dis 9:11–23

    Article  PubMed  CAS  Google Scholar 

  60. Kojro E, Gimpl G, Lammich S, Marz W, Fahrenholz F (2001) Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha-secretase ADAM 10. Proc Natl Acad Sci U S A 98:5815–5820

    Article  PubMed  CAS  Google Scholar 

  61. Abad-Rodriguez J, Ledesma MD, Craessaerts K, Perga S, Medina M, Delacourte A, Dingwall C, De Strooper B, Dotti CG (2004) Neuronal membrane cholesterol loss enhances amyloid peptide generation. J Cell Biol 167:953–960

    Article  PubMed  CAS  Google Scholar 

  62. Ehehalt R, Keller P, Haass C, Thiele C, Simons K (2003) Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts. J Cell Biol 160:113–123

    Article  PubMed  CAS  Google Scholar 

  63. Kirsch C, Eckert GP, Mueller WE (2003) Statin effects on cholesterol micro-domains in brain plasma membranes. Biochem Pharmacol 65:843–856

    Article  PubMed  CAS  Google Scholar 

  64. Park IH, Hwang EM, Hong HS, Boo JH, Oh SS, Lee J, Jung MW, Bang OY, Kim SU, Mook-Jung I (2003) Lovastatin enhances Abeta production and senile plaque deposition in female Tg2576 mice. Neurobiol Aging 24:637–643

    Article  PubMed  CAS  Google Scholar 

  65. Howland DS, Trusko SP, Savage MJ, Reaume AG, Lang DM, Hirsch JD, Maeda N, Siman R, Greenberg BD, Scott RW, Flood DG (1998) Modulation of secreted beta-amyloid precursor protein and amyloid beta-peptide in brain by cholesterol. J Biol Chem 273:16576–16582

    Article  PubMed  CAS  Google Scholar 

  66. Kalvodova L, Kahya N, Schwille P, Ehehalt R, Verkade P, Drechsel D, Simons K (2005) Lipids as modulators of proteolytic activity of BACE—Involvement of cholesterol, glycosphingolipids, and anionic phospholipids in vitro. J Biol Chem 280:36815–36823

    Article  PubMed  CAS  Google Scholar 

  67. Fukumoto H, Deng A, Irizarry MC, Fitzgerald ML, Rebeck GW (2002) Induction of the cholesterol transporter ABCA1 in central nervous system cells by Liver X receptor agonists increases secreted Abeta levels. J Biol Chem 277:48508–48513

    Article  PubMed  CAS  Google Scholar 

  68. Brown J III, Theisler C, Silberman S, Magnuson D, Gottardi-Littell N, Lee JM, Yager D, Crowley J, Sambamurti K, Rahman MM, Reiss AB, Eckman CB, Wolozin B (2004) Differential expression of cholesterol hydroxylases in Alzheimer’s disease. J Biol Chem 279:34674–34681

    Article  PubMed  CAS  Google Scholar 

  69. Puglielli L, Konopka G, Pack-Chung E, Ingano LA, Berezovska O, Hyman BT, Chang TY, Tanzi RE, Kovacs DM (2001) Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid beta-peptide. Nat Cell Biol 3:905–912

    Article  PubMed  CAS  Google Scholar 

  70. Hutter-Paier B, Huttunen HJ, Puglielli L, Eckman CB, Kim DY, Hofmeister A, Moir RD, Domnitz SB, Frosch MP, Windisch M, Kovacs DM (2004) The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer’s disease. Neuron 44:227–238

    Article  PubMed  CAS  Google Scholar 

  71. Zandi PP, Sparks DL, Khachaturian AS, Tschanz J, Norton M, Steinberg M, Welsh-Bohmer KA, Breitner JC (2005) Do statins reduce risk of incident dementia and Alzheimer disease? The Cache County Study. Arch Gen Psychiatry 62:217–224

    Article  PubMed  CAS  Google Scholar 

  72. Wolozin B (2004) Cholesterol, statins and dementia. Curr Opin Lipidol 15:667–672

    Article  PubMed  CAS  Google Scholar 

  73. Locatelli S, Lütjohann D, Schmidt HH, Otto C, Beisiegel U, von Bergmann K (2002) 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. Arch Neurol 59:213–216

    Article  PubMed  Google Scholar 

  74. Vega GL, Weiner MF, Lipton AM, von Bergmann K, Lütjohann D, Moore C, Svetlik D (2003) Reduction in levels of 24S-hydroxycholesterol by statin treatment in patients with Alzheimer disease. Arch Neurol 60:510–515

    Article  PubMed  Google Scholar 

  75. Botti RE, Triscari J, Pan HY, Zayat J (1991) Concentrations of pravastatin and lovastatin in cerebrospinal fluid in healthy subjects. Clin Neuropharmacol 14:256–261

    Article  PubMed  CAS  Google Scholar 

  76. Heverin M, Meaney S, Lütjohann D, Diczfalusy U, Wahren J, Björkhem I (2005) Crossing the barrier: net flux of 27-hydroxycholesterol into the human brain. J Lipid Res 46:1047–1052

    Article  PubMed  CAS  Google Scholar 

  77. Michikawa M (2003) Cholesterol paradox: is high total or low HDL cholesterol level a risk for Alzheimer’s disease? J Neurosci Res 72:141–146

    Article  PubMed  CAS  Google Scholar 

  78. Launer LJ, White LR, Petrovitch H, Ross GW, Curb JD (2001) Cholesterol and neuropathologic markers of AD: a population-based autopsy study. Neurology 57:1447–1452

    PubMed  CAS  Google Scholar 

  79. Burns MP, Igbavboa U, Wang LL, Wood WG, Duff K (2006) Cholesterol distribution, not total levels, correlate with altered amyloid precursor, protein processing in statin-treated mice. Neuromol Med 8:319–328

    Article  CAS  Google Scholar 

  80. Paiva H, Thelen KM, Van Coster R, Smet J, De Paepe B, Mattila KM, Laakso J, Lehtimaki T, von Bergmann K, Lütjohann D, Laaksonen R (2005) High-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial. Clin Pharmacol Ther 78:60–68

    Article  PubMed  CAS  Google Scholar 

  81. Cordle A, Koenigsknecht-Talboo J, Wilkinson B, Limpert A, Landreth G (2005) Mechanisms of statin-mediated inhibition of small G-protein function. J Biol Chem 280:34202–34209

    Article  PubMed  CAS  Google Scholar 

  82. Endres M, Laufs U (2004) Effects of statins on endothelium and signaling mechanisms. Stroke 35:2708–2711

    Article  PubMed  CAS  Google Scholar 

  83. Nakagami H, Jensen KS, Liao JK (2003) A novel pleiotropic effect of statins: prevention of cardiac hypertrophy by cholesterol-independent mechanisms. Ann Med 35:398–403

    Article  PubMed  CAS  Google Scholar 

  84. Kuipers HF, Rappert AA, Mommaas AM, van Haastert ES, van der Vack P, Boddeke HW, Biber KP, van den Elsen PJ (2006) Simvastatin affects cell motility and actin cytoskeleton distribution of microglia. Glia 53:115–123

    Article  PubMed  Google Scholar 

  85. Tanaka K, Honda M, Takabatake T (2004) Anti-apoptotic effect of atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, on cardiac myocytes through protein kinase C activation. Clin Exp Pharmacol Physiol 31:360–364

    Article  PubMed  CAS  Google Scholar 

  86. Cole SL, Grudzien A, Manhart IO, Kelly BL, Oakley H, Vassar R (2005) Statins cause intracellular accumulation of amyloid precursor protein, beta-secretase-cleaved fragments, and amyloid beta-peptide via an isoprenoid-dependent mechanism. J Biol Chem 280:18755–18770

    Article  PubMed  CAS  Google Scholar 

  87. Wolozin B, Manger J, Bryant R, Cordy J, Green RC, McKee A (2006) Re-assessing the relationship between cholesterol, statins and Alzheimer’s disease. Acta Neurol Scand Suppl 185:63–70

    Article  PubMed  CAS  Google Scholar 

  88. Refolo LM, Pappolla MA, LaFrancois J, Malester B, Schmidt SD, Thomas-Bryant T, Tint GS, Wang R, Mercken M, Petanceska SS, Duff KE (2001) A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer’s disease. Neurobiol Dis 8:890–899

    Article  PubMed  CAS  Google Scholar 

  89. Johnson-Anuna LN, Eckert GP, Keller JH, Igbavboa U, Franke C, Fechner T, Schubert-Zsilavecz M, Karas M, Müller WE, Wood WG (2005) Chronic administration of statins alters multiple gene expression patterns in mouse cerebral cortex. J Pharmacol Exp Therapeut 312:786–793

    Article  CAS  Google Scholar 

  90. Nixon RA (2004) Niemann-Pick type C disease and Alzheimer’s disease - The APP-endosome connection fattens up. Am J Pathol 164:757–761

    PubMed  Google Scholar 

  91. Burns M, Duff K (2003) Use of in vivo models to study the role of cholesterol in the etiology of Alzheimer’s disease. Neurochem Res 28:979–986

    Article  PubMed  CAS  Google Scholar 

  92. Yamazaki T, Chang TY, Haass C, Ihara Y (2001) Accumulation and aggregation of amyloid beta-protein in late endosomes of Niemann-pick type C cells. J Biol Chem 276:4454–4460

    Article  PubMed  CAS  Google Scholar 

  93. Kremer JJ, Sklansky DJ, Murphy RM (2001) Profile of changes in lipid bilayer structure caused by beta-amyloid peptide. Biochemistry 40:8563–8571

    Article  PubMed  CAS  Google Scholar 

  94. Mizuno T, Nakata M, Naiki H, Michikawa M, Wang R, Haass C, Yanagisawa K (1999) Cholesterol-dependent generation of a seeding amyloid beta-protein in cell culture. J Biol Chem 274:15110–15114

    Article  PubMed  CAS  Google Scholar 

  95. Arispe N, Doh M (2002) Plasma membrane cholesterol controls the cytotoxicity of Alzheimer’s disease A beta P (1–40) and (1–42) peptides. Faseb J 16:1526–1536

    Article  PubMed  CAS  Google Scholar 

  96. Hartmann H, Eckert A, Müller WE (1994) Apolipoprotein-E and cholesterol affect neuronal calcium signaling—the possible relationship to beta-amyloid neurotoxicity. Biochem Biophys Res Commun 200:1185–1192

    Article  PubMed  CAS  Google Scholar 

  97. Kawahara M, Kuroda Y (2001) Intracellular calcium changes in neuronal cells induced by Alzheimer’s beta-amyloid protein are blocked by estradiol and cholesterol. Cell Mol Neurobiol 21:1–13

    Article  PubMed  CAS  Google Scholar 

  98. Zhou Y, Richardson JS (1996) Cholesterol protects PC12 cells from beta-amyloid induced calcium disordering and cytotoxicity. Neuroreport 7:2487–2490

    Article  PubMed  CAS  Google Scholar 

  99. Subasinghe S, Unabia S, Barrow CJ, Mok SS, Aguilar MI, Small DH (2003) Cholesterol is necessary both for the toxic effect of Abeta peptides on vascular smooth muscle cells and for Abeta binding to vascular smooth muscle cell membranes. J Neurochem 84:471–479

    Article  PubMed  CAS  Google Scholar 

  100. Micelli S, Meleleo D, Picciarelli V, Gallucci E (2004) Effect of sterols on beta-amyloid peptide (AbetaP 1–40) channel formation and their properties in planar lipid membranes. Biophys J 86:2231–2237

    Article  PubMed  CAS  Google Scholar 

  101. Bieschke J, Zhang Q, Powers ET, Lerner RA, Kelly JW (2005) Oxidative metabolites accelerate Alzheimer’s amyloidogenesis by a two-step mechanism, eliminating the requirement for nucleation. Biochemistry 44:4977–4983

    Article  PubMed  CAS  Google Scholar 

  102. Schneider A, Schulz-Schaeffer W, Hartmann T, Schulz JB, Simons M (2006) Cholesterol depletion reduces aggregation of amyloid-beta peptide in hippocampal neurons. Neurobiol Dis 23:573–577

    Article  PubMed  CAS  Google Scholar 

  103. Sponne I, Fifre A, Koziel V, Oster T, Olivier JL, Pillot T (2004) Membrane cholesterol interferes with neuronal apoptosis induced by soluble oligomers but not fibrils of amyloid-beta peptide. FASEB J 18:836–838

    PubMed  CAS  Google Scholar 

  104. Eckert GP, Kirsch C, Leutz S, Wood WG, Müller WE (2003) Cholesterol modulates amyloid beta-peptide’s membrane interactions. Pharmacopsychiatry 36(Suppl 2):S136–S143

    PubMed  CAS  Google Scholar 

  105. Gibson-Wood W, Eckert GP, Igbavboa U, Müller WE (2003) Amyloid beta-protein interactions with membranes and cholesterol: causes or casualties of Alzheimer’s disease. Biochim Biophys Acta 1610:281–290

    Article  PubMed  CAS  Google Scholar 

  106. Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatanpaa K, Troncoso JC, Mattson MP (2004) Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer’s disease. Proc Natl Acad Sci U S A 101:2070–2075

    Article  PubMed  CAS  Google Scholar 

  107. Malaplate-Armand C, Florent-Bechard S, Youssef I, Koziel V, Sponne I, Kriem B, Leininger-Muller B, Olivier JL, Oster T, Pillot T (2006) Soluble oligomers of amyloid-beta peptide induce neuronal apoptosis by activating a cPLA(2)-dependent sphingomyelinase-ceramide pathway. Neurobiol Dis 23:178–189

    Article  PubMed  CAS  Google Scholar 

  108. Grimm MO, Grimm HS, Patzold AJ, Zinser EG, Halonen R, Duering M, Tschape JA, De Strooper B, Muller U, Shen J, Hartmann T (2005) Regulation of cholesterol and sphingomyelin metabolism by amyloid-beta and presenilin. Nat Cell Biol 7:1118–1123

    PubMed  CAS  Google Scholar 

  109. Grimm MOW, Tschape JA, Grimm HS, Zinser EG, Hartmann T (2006) Altered membrane fluidity and lipid raft composition in presenilin-deficient cells. Acta Neurologica Scandinavica 114:27–32

    Article  Google Scholar 

  110. Tang MX, Maestre G, Tsai WY, Liu XH, Feng L, Chung WY, Chun M, Schofield P, Stern Y, Tycko B, Mayeux R (1996) Relative risk of Alzheimer disease and age-at-onset distributions, based on APOE genotypes among elderly African Americans, Caucasians, and Hispanics in New York City. Am J Hum Genet 58:574–584

    PubMed  CAS  Google Scholar 

  111. Schupf N, Sergievsky GH (2002) Genetic and host factors for dementia in Down’s syndrome. Br J Psychiatry 180:405–410

    Article  PubMed  Google Scholar 

  112. Nicoll JA, Roberts GW, Graham DI (1995) Apolipoprotein E epsilon 4 allele is associated with deposition of amyloid beta-protein following head injury. Nat Med 1:135–137

    Article  PubMed  CAS  Google Scholar 

  113. Liu Y, Laakso MP, Karonen JO, Vanninen RL, Nuutinen J, Soimakallio S, Aronen HJ (2002) Apolipoprotein E polymorphism and acute ischemic stroke: a diffusion- and perfusion-weighted magnetic resonance imaging study. J Cereb Blood Flow Metab 22:1336–1342

    Article  PubMed  CAS  Google Scholar 

  114. Horsburgh K, McCulloch J, Nilsen M, Roses AD, Nicoll JA (2000) Increased neuronal damage and apoE immunoreactivity in human apolipoprotein E, E4 isoform-specific, transgenic mice after global cerebral ischaemia. Eur J Neurosci 12:4309–4317

    Article  PubMed  CAS  Google Scholar 

  115. Sing CF, Davignon J (1985) Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation. Am J Hum Genet 37:268–285

    PubMed  CAS  Google Scholar 

  116. Nagy Z, Esiri MM, Jobst KA, Johnston C, Litchfield S, Sim E, Smith AD (1995) Influence of the apolipoprotein E genotype on amyloid deposition and neurofibrillary tangle formation in Alzheimer’s disease. Neuroscience 69:757–761

    Article  PubMed  CAS  Google Scholar 

  117. McNamara MJ, Gomez-Isla T, Hyman BT (1998) Apolipoprotein E genotype and deposits of Abeta40 and Abeta42 in Alzheimer disease. Arch Neurol 55:1001–1004

    Article  PubMed  CAS  Google Scholar 

  118. Gibson GE, Haroutunian V, Zhang H, Park LC, Shi Q, Lesser M, Mohs RC, Sheu RK, Blass JP (2000) Mitochondrial damage in Alzheimer’s disease varies with apolipoprotein E genotype. Ann Neurol 48:297–303

    Article  PubMed  CAS  Google Scholar 

  119. Rapp A, Gmeiner B, Huttinger M (2006) Implication of apoE isoforms in cholesterol metabolism by primary rat hippocampal neurons and astrocytes. Biochimie 88:473–483

    Article  PubMed  CAS  Google Scholar 

  120. Michikawa M, Fan QW, Isobe I, Yanagisawa K (2000) Apolipoprotein E exhibits isoform-specific promotion of lipid efflux from astrocytes and neurons in culture. J Neurochem 74:1008–1016

    Article  PubMed  CAS  Google Scholar 

  121. Stratman NC, Castle CK, Taylor BM, Epps DE, Melchior GW, Carter DB (2005) Isoform-specific interactions of human apolipoprotein E to an intermediate conformation of human Alzheimer amyloid-beta peptide. Chem Phys Lipids 137:52–61

    Article  PubMed  CAS  Google Scholar 

  122. Buttini M, Orth M, Bellosta S, Akeefe H, Pitas RE, Wyss-Coray T, Mucke L, Mahley RW (1999) Expression of human apolipoprotein E3 or E4 in the brains of ApoE-/- mice: isoform-specific effects on neurodegeneration. J Neurosci 19:4867–4880

    PubMed  CAS  Google Scholar 

  123. Keller JN, Lauderback CM, Butterfield DA, Kindy MS, Yu J, Markesbery WR (2000) Amyloid beta-peptide effects on synaptosomes from apolipoprotein E-deficient mice. J Neurochem 74:1579–1586

    Article  PubMed  CAS  Google Scholar 

  124. Jordan J, Galindo MF, Miller RJ, Reardon CA, Getz GS, LaDu MJ (1998) Isoform-specific effect of apolipoprotein E on cell survival and beta-amyloid-induced toxicity in rat hippocampal pyramidal neuronal cultures. J Neurosci 18:195–204

    PubMed  CAS  Google Scholar 

  125. LaDu MJ, Pederson TM, Frail DE, Reardon CA, Getz GS, Falduto MT (1995) Purification of apolipoprotein E attenuates isoform-specific binding to beta-amyloid. J Biol Chem 270:9039–9042

    Article  PubMed  CAS  Google Scholar 

  126. Lane RM, Farlow MR (2005) Lipid homeostasis and apolipoprotein E in the development and progression of Alzheimer’s disease. J Lipid Res 46:949–968

    Article  PubMed  CAS  Google Scholar 

  127. Huang Y (2006) Apolipoprotein E and Alzheimer disease. Neurology 66:S79-S85

    Article  PubMed  CAS  Google Scholar 

  128. Crutcher KA (2004) Apolipoprotein E is a prime suspect, not just an accomplice, in Alzheimer’s disease. J Mol Neurosci 23:181–188

    Article  PubMed  CAS  Google Scholar 

  129. Chang S, ran MT, Miranda RD, Balestra ME, Mahley RW, Huang Y (2005) Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity. Proc Natl Acad Sci USA 102:18694–18699

    Article  PubMed  CAS  Google Scholar 

  130. Mahley RW, Weisgraber KH, Huang Y (2006) Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc Natl Acad Sci USA 103:5644–5651

    Article  PubMed  CAS  Google Scholar 

  131. Walsh DT, Montero RM, Bresciani LG, Jen AY, Leclercq PD, Saunders D, EL-Amir AN, Gbadamoshi L, Gentleman SM, Jen LS (2002) Amyloid-beta peptide is toxic to neurons in vivo via indirect mechanisms. Neurobiol Dis 10:20–27

    Article  PubMed  CAS  Google Scholar 

  132. Abramov AY, Canevari L, Duchen MR (2003) Changes in intracellular calcium and glutathione in astrocytes as the primary mechanism of amyloid neurotoxicity. J Neurosci 23:5088–5095

    PubMed  CAS  Google Scholar 

  133. Quist A, Doudevski I, Lin H, Azimova R, Ng D, Frangione B, Kagan B, Ghiso J, Lal R (2005) Amyloid ion channels: a common structural link for protein-misfolding disease. Proc Natl Acad Sci U S A 102:10427–10432

    Article  PubMed  CAS  Google Scholar 

  134. Abramov AY, Canevari L, Duchen MR (2004) Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J Neurosci 24:565–575

    Article  PubMed  CAS  Google Scholar 

  135. Abramov AY, Jacobson J, Wientjes F, Hothersall J, Canevari L, Duchen MR (2005) Expression and modulation of an NADPH oxidase in mammalian astrocytes. J Neurosci 25:9176–9184

    Article  PubMed  CAS  Google Scholar 

  136. Keelan J, Allen NJ, Antcliffe D, Pal S, Duchen MR (2001) Quantitative imaging of glutathione in hippocampal neurons and glia in culture using monochlorobimane. J Neurosci Res 66:873–884

    Article  PubMed  CAS  Google Scholar 

  137. DellaBianca V, Dusi S, Bianchini E, Dal P I, Rossi F (1999) beta-amyloid activates the O- 2 forming NADPH oxidase in microglia, monocytes, and neutrophils. A possible inflammatory mechanism of neuronal damage in Alzheimer’s disease. J Biol Chem 274:15493–15499

    Article  CAS  Google Scholar 

  138. Shimohama S, Tanino H, Kawakami N, Okamura N, Kodama H, Yamaguchi T, Hayakawa T, Nunomura A, Chiba S, Perry G, Smith MA, Fujimoto S (2000) Activation of NADPH oxidase in Alzheimer’s disease brains. Biochem Biophys Res Commun 273:5–9

    Article  PubMed  CAS  Google Scholar 

  139. Shao D, Segal AW, Dekker LV (2003) Lipid rafts determine efficiency of NADPH oxidase activation in neutrophils. FEBS Lett 550:101–106

    Article  PubMed  CAS  Google Scholar 

  140. Vilhardt F, van Deurs B (2004) The phagocyte NADPH oxidase depends on cholesterol-enriched membrane microdomains for assembly. EMBO J 23:739–748

    Article  PubMed  CAS  Google Scholar 

  141. Nakagami H, Jensen KS, Liao JK (2003) A novel pleiotropic effect of statins: prevention of cardiac hypertrophy by cholesterol-independent mechanisms. Ann Med 35:398–403

    Article  PubMed  CAS  Google Scholar 

  142. Rosenblat M, Aviram M (2002) Oxysterol-induced activation of macrophage NADPH-oxidase enhances cell-mediated oxidation of LDL in the atherosclerotic apolipoprotein E deficient mouse: inhibitory role for vitamin E. Atherosclerosis 160:69–80

    Article  PubMed  CAS  Google Scholar 

  143. Jana A, Pahan K (2004) Fibrillar amyloid-beta peptides kill human primary neurons via NADPH oxidase-mediated activation of neutral sphingomyelinase. Implications for Alzheimer’s disease. J Biol Chem 279:51451–51459

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

We wish to thank the Miriam Marks fund for supporting LC and the Division of Neurochemistry.

Author information

Authors and Affiliations

  1. Miriam Marks Division of Neurochemistry, Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London, UK

    Laura Canevari & John B. Clark

  2. Department of Cellular and Molecular Neuroscience, Division of Neuroscience and Mental Health, Imperial College, Charing Cross Hospital Campus, St. Dunstan’s Road, London, W6 8RP, UK

    Laura Canevari

Authors
  1. Laura Canevari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John B. Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Laura Canevari.

Additional information

Special issue dedicated to John P. Blass.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Canevari, L., Clark, J.B. Alzheimer’s Disease and Cholesterol: The Fat Connection. Neurochem Res 32, 739–750 (2007). https://doi.org/10.1007/s11064-006-9200-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-006-9200-1

Keywords

Search

Navigation