Statins: Drugs for Alzheimer's disease?

Journal of Neural Transmission

Volumn 112, Issue 8, 2005, Pages 1057-1071

  Eckert, G P ^a   Wood, W G ^b   Muller W E ^a  

^a GOETHE UNIVERSITY   (Germany)

^b UNIVERSITY OF MINNESOTA MEDICAL SCHOOL   (United States)

Author keywords

Alzheimer's disease; Brain; Cholesterol; Statins

Indexed keywords

4 [2 [1 (4 CHLOROCINNAMYL) 4 PIPERAZINYL]ETHYL]BENZOIC ACID; AMYLOID BETA PROTEIN; AMYLOID PRECURSOR PROTEIN; ANTILIPEMIC AGENT; ATORVASTATIN; CERIVASTATIN; CHOLESTEROL; DONEPEZIL; FLUINDOSTATIN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; HYPOCHOLESTEROLEMIC AGENT; IBUPROFEN; METHYL BETA CYCLODEXTRIN; MEVINOLIN; NONSTEROID ANTIINFLAMMATORY AGENT; PRAVASTATIN; RPR 107393; SIMVASTATIN; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; AMNESIA; AMYLOIDOSIS; CELL CULTURE; CHOLESTEROL BLOOD LEVEL; CLINICAL TRIAL; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG BRAIN LEVEL; DRUG EFFECT; DRUG EFFICACY; DRUG MEGADOSE; DRUG PENETRATION; DRUG SAFETY; HUMAN; HYPERCHOLESTEROLEMIA; LEARNING DISORDER; NEUROTOXICITY; NONHUMAN; PREVALENCE; PRIORITY JOURNAL; REVIEW; RISK FACTOR;

ALZHEIMER DISEASE; AMYLOID BETA-PROTEIN; ANIMALS; BRAIN; CHOLESTEROL; CLINICAL TRIALS; HUMANS; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; HYPERCHOLESTEROLEMIA; TREATMENT OUTCOME;

EID: 22244452701     PISSN: 03009564     EISSN: None     Source Type: Journal    
DOI: 10.1007/s00702-004-0273-1     Document Type: Review

References (74)

1. Algotsson A, Winblad B (2004) Patients with Alzheimer's disease may be particularly susceptible to adverse effects of statins. Dement Geriatr Cogn Disord 17: 109-116
2. Bellosta S, Ferri N, Bernini F, Paoletti R, Corsini A (2000) Non-lipid-related effects of statins. Ann Med 32: 164-176
3. 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
4. Bodovitz S, Klein WL (1996) Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein. J Biol Chem 271: 4436-4440
5. Bossy-Wetzel E, Schwarzenbacher R, Lipton SA (2004) Molecular pathways to neurodegeneration. Nat Med 10 (Suppl): S2-S9
6. 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
7. Breitner JCS, Zandi PP, Li G, Rea TG, Psaty BM (2004) Can statins prevent AD, or are they just prescribed less often to those with cognitive disorders? Neurobiol Aging 25 [S2]: 5
8. Buxbaum JD, Geoghagen NS, Friedhoff LT (2001) Cholesterol depletion with physiological concentrations of a statin decreases the formation of the Alzheimer amyloid Abeta peptide. J Alzheimers Dis 3: 221-229
9. Cole SL, Grudzien A, Manhart I, Kelly B, Oakley H, Vassar R (2004) A tale of two statins: the effects of lovastatin and simvastatin on app metabolism. Neurobiol Aging 25[S2]: 77
10. Corsini A, Bellosta S, Baetta R, Fumagalli R, Paoletti R, Bernini F (1999) New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther 84: 413-428
11. Dietschy JM, Turley SD (2002) Control of cholesterol turnover in the mouse. J Biol Chem 277: 3801-3804
12. Dietschy JM, Turley SD (2004) Thematic review series: Brain lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res 45: 1375-1397
13. Doraiswamy PM, Steffens D, McQuoid D (2004) Statin use and hippocampal volume in subjects at risk for Alzheimer's disease. Neurobiol Aging 45[S2]: 13
14. Eckert GP, Kirsch C, Müller WE (2001) Differential effects of lovastatin treatment on brain cholesterol levels in normal and apoE-deficient mice. Neuroreport 12: 883-887
15. Eckert GP, Igbavboa U, Müller WE, Wood WG (2003a) Lipid rafts of purified mouse brain synaptosomes prepared with or without detergent reveal different lipid and protein domains. Brain Res 962: 144-150
16. Eckert GP, Kirsch C, Leutz S, Wood WG, Müller WE (2003b) Cholesterol modulates amyloid beta-peptide's membrane interactions. Pharmacopsychiatry 36 (Suppl 2): S136-S143
17. Eckert GP, Keller JH, Weber CC, Franke C, Peters I, Karas M, Schubert-Zsilavecz M, Müller WE (2004) Brain availability and effects on lipid homeostasis of statins. Neurobiol Aging 25[S2]: 579
18. Farnier M, Davignon J (1998) Current and future treatment of hyperlipidemia: the role of statins. Am J Cardiol 82: 3J-10J
19. Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann 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 USA 98: 5856-5861
20. Fassbender K, Stroick M, Bertsch T, Ragoschke A, Kuehl S, Walter S, Walter J, Brechtel K, Muehlhauser F, von Bergmann K, Lutjohann D (2002) Effects of statins on human cerebral cholesterol metabolism and secretion of Alzheimer amyloid peptide. Neurology 59: 1257-1258
21. Frears ER, Stephens DJ, Walters CE, Davies H, Austen BM (1999) The role of cholesterol in the biosynthesis of beta-amyloid. Neuroreport 10: 1699-1705
22. Friedhoff LT, Cullen EI, Geoghagen NS, Buxbaum JD (2001) Treatment with controlled-release lovastatin decreases serum concentrations of human beta-amyloid (A beta) peptide. Int J Neuropsychopharmacol 4: 127-130
23. Gong JS, Sawamura N, Zou K, Sakai J, Yanagisawa K, Michikawa M (2002) Amyloid beta-protein affects cholesterol metabolism in cultured neurons: implications for pivotal role of cholesterol in the amyloid cascade. J Neurosci Res 70: 438-446
24. Hajjar I, Schumpert J, Hirth V, Wieland D, Eleazer GP (2002) The impact of the use of statins on the prevalence of dementia and the progression of cognitive impairment. J Gerontol A Biol Sci Med Sci 57: M414-M418
25. Hamelin BA, Turgeon J (1998) Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol Sci 19: 26-37
26. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297: 353-356
27. Hoglund K, Wiklund O, Vanderstichele H, Eikenberg O, Vanmechelen E, Blennow K (2004) Plasma levels of beta-amyloid(1-40), beta-amyloid(1-42), and total beta-amyloid remain unaffected in adult patients with hypercholesterolemia after treatment with statins. Arch Neurol 61: 333-337
28. 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
29. Igbavboa U, Pidcock JM, Johnson LN, Malo TM, Studniski AE, Yu S, Sun GY, Wood WG (2003) Cholesterol distribution in the Golgi complex of astrocytes is differentially altered by fresh and aged amyloid beta-peptide1-42. J Biol Chem 278: 17150-17157
30. Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA (2000) Statins and the risk of dementia. Lancet 356: 1627-1631
31. Johnson-Anuna LN, Eckert GP, Keller JH, Igbavboa U, Franke C, Fechner T, Schubert-Zsilavecz M, Karas M, Muller WE, Wood WG (2005) Chronic administration of statins alters multiple gene expression patterns in mouse cerebral cortex. J Pharmacol Exp Ther 312: 786-793
32. Kabouridis PS, Janzen J, Magee AL, Ley SC (2000) Cholesterol depletion disrupts lipid rafts and modulates the activity of multiple signaling pathways in T lymphocytes. Eur J Immunol 30: 954-963
33. Kirsch C, Eckert GP, Müller WE (2002) Cholesterol attenuates the membrane perturbing properties of β-amyloid peptides. Amyloid 9: 149-159
34. Kirsch C, Eckert GP, Koudinov AR, Muller WE (2003a) Brain cholesterol, statins and Alzheimer's disease. Pharmacopsychiatry 36 (Suppl 2): S113-S119
35. Kirsch C, Eckert GP, Müller WE (2003b) Statins affect cholesterol micro-domains in brain plasma membranes. Biochem Pharmacol 65: 843-856
36. 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 USA 98: 5815-5820
37. Kölsch H, Lutjohann 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
38. Koudinov AR, Koudinova NV (2001) Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J 15: 1858-1860
39. Li L, Cao D, Wan H, Chen J (2004) Enhancement of learning and memory by statins beyond Alzheimer's disease. Neurobiol Aging 25[S2]: 82
40. Liscum L, Munn NJ (1999) Intracellular cholesterol transport. Biochim Biophys Acta 1438: 19-37
41. 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
42. Lousberg TR, Denham AM, Rasmussen JR (2001) A comparison of clinical outcome studies among cholesterol-lowering agents. Ann Pharmacother 35: 1599-1607
43. Lütjohann D, Papassotiropoulos A, Bjorkhem I, Locatelli S, Bagli M, Oehring RD, Schlegel U, Jessen F, Rao ML, von Bergmann K, Heun R (2000) Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients. J Lipid Res 41: 195-198
44. Meske V, Albert F, Richter D, Schwarze J, Ohm TG (2003) Blockade of HMG-CoA reductase activity causes changes in microtubule-stabilizing protein tau via suppression of geranylgeranylpyrophosphate formation: implications for Alzheimer's disease. Eur J Neurosci 17: 93-102
45. Michikawa M (2003) The role of cholesterol in pathogenesis of Alzheimer's disease: dual metabolic interaction between amyloid beta-protein and cholesterol. Mol Neurobiol 27: 1-12
46. Ohm TG, Treiber-Held S, Distl R, Glockner F, Schonheit B, Tamanai M, Meske V (2003) Cholesterol and tau protein-findings in Alzheimer's and Niemann Pick C's disease. Pharmacopsychiatry 36 (Suppl 2): S120-S126
47. Papassotiropoulos A, Lutjohann D, Bagli M, Locatelli S, Jessen F, Buschfort R, Ptok U, Bjorkhem I, von Bergmann K, Heun R (2002) 24S-hydroxycholesterol in cerebrospinal fluid is elevated in early stages of dementia. J Psychiatr Res 36: 27-32
48. 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
49. Parvathy S, Ehrlich M, Pedrini S, Diaz N, Refolo L, Buxbaum JD, Bogush A, Petanceska S, Gandy S (2004) Atorvastatin-induced activation of Alzheimer's alpha secretase is resistant to standard inhibitors of protein phosphorylation-regulated ectodomain shedding. J Neurochem 90: 1005-1010
50. Petanceska SS, DeRosa S, Olm V, Diaz N, Sharma A, Thomas-Bryant T, Duff K, Pappolla M, Refolo LM (2002) Stalin therapy for Alzheimer's disease: will it work? J Mol Neurosci 19: 155-161
51. Pike CJ, Walencewicz AJ, Glabe CG, Cotman CW (1991) Aggregation-related toxicity of synthetic beta-amyloid protein in hippocampal cultures. Eur J Pharmacol 207: 367-368
52. Pradier L, Canton T, Bouaiche Z, Benoit P, Benavides J (2004) The squalene synthase inhibitor RPR 107393A reduces Aβ peptide level in an APP transgenic mouse model. Neurobiol Aging 25[25]: 568
53. Refolo LM, Pappolla MA, Malester B, LaFrancois J, Bryant-Thomas T, Wang R, Tint GS, Sambamurti K, Duff K (2000) Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol Dis 7: 321-331
54. 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
55. Rockwood K, Kirkland S, Hogan DB, MacKnight C, Merry H, Verreault R, Wolfson C, McDowell I (2002) Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch Neurol 59: 223-227
56. Saheki A, Terasaki T, Tamai I, Tsuji A (1994) In vivo and in vitro blood-brain barrier transport of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Pharm Res 11: 305-311
57. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, Kamper AM, Macfarlane PW, Meinders AE, Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ, Twomey C, Westendorp RG (2002) Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 360: 1623-1630
58. Simons K, Ehehalt R (2002) Cholesterol, lipid rafts, and disease. J Clin Invest 110: 597-603
59. 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
60. Simons M, Schwarzler F, Lutjohann 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
61. Sparks DL, Scheff SW, Hunsaker JC, 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
62. 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
63. Wagstaff LR, Mitton MW, Arvik BM, Doraiswamy PM (2003) Statin-associated memory loss: analysis of 60 case reports and review of the literature. Pharmacotherapy 23: 871-880
64. 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
65. Wolozin B (2001) A fluid connection: cholesterol and Abeta. Proc Natl Acad Sci USA 98: 5371-5373
66. Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G (2000) Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arch Neurol 57: 1439-1443
67. Wolozin B, Brown J, III, Theisler C, Silberman S (2004) The cellular biochemistry of cholesterol and statins: insights into the pathophysiology and therapy of Alzheimer's disease. CNS Drug Rev 10: 127-146
68. Wood WG, Schroeder F, Igbavboa U, Avdulov NA, Chochina SV (2002) Brain membrane cholesterol domains, aging and amyloid beta-peptides. Neurobiol Aging 23: 685
69. Wood WG, 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
70. Wood WG, Igbavboa U, Eckert GP, Johnson-Anuna LN, Franke C, Müller WE (2004) Is hypercholesterolemia a risk factor for Alzheimer's disease? Mol Neurobiol (in press)
71. Yankner BA, Duffy LK, Kirschner DA (1990) Neurotrophic and neurotoxic effects of amyloid-beta protein: reversal by tachykinin neuropeptides. Science 250: 279-282
72. Yao ZX, Papadopoulos V (2002) Function of β-amyloid in cholesterol transport: a lead to neurotoxicity. FASEB J 16: 1677-1679
73. Zacco A, Togo J, Spence K, Ellis A, Lloyd D, Furlong S, Piser T (2003) 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors protect cortical neurons from excitotoxicity. J Neurosci 23: 11104-11111
74. Zamrini E, McGwin G, Roseman JM (2004) Association between statin use and Alzheimer's disease. Neuroepidemiology 23: 94-98