The complex actions of statins in brain and their relevance for Alzheimer’s disease treatment: An analytical review

Current Alzheimer Research

Volumn 11, Issue 9, 2014, Pages 817-833

  Mendoza Oliva, Aydé ^a   Zepeda, Angélica ^a   Arias, Clorinda ^a  

^a UNIVERSIDAD NACIONAL AUTÓNOMA DE MÉXICO   (Mexico)

Author keywords

Alzheimer's disease; Amyloid beta; Cholesterol pathway; HMG CoA reductase; Isoprenoids; Neuroprotection; Neurotoxicity; Statins

Indexed keywords

COMPACTIN; FLUINDOSTATIN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; ISOPRENOID; MEVINOLIN; PRAVASTATIN; ROSUVASTATIN; SIMVASTATIN; CHOLESTEROL; NEUROPROTECTIVE AGENT;

ALZHEIMER DISEASE; ANTIOXIDANT ACTIVITY; ARTICLE; BRAIN METABOLISM; CHOLESTEROL METABOLISM; CHOLESTEROL SYNTHESIS; EXCITOTOXICITY; HOMEOSTASIS; HUMAN; NERVOUS SYSTEM INFLAMMATION; NEUROTOXICITY; NONHUMAN; ANIMAL; BIOSYNTHESIS; BRAIN; DRUG EFFECTS; METABOLISM;

ALZHEIMER DISEASE; ANIMALS; BRAIN; CHOLESTEROL; HUMANS; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; NEUROPROTECTIVE AGENTS;

EID: 84911441075     PISSN: 15672050     EISSN: 18755828     Source Type: Journal    
DOI: 10.2174/1567205011666141001114858     Document Type: Article

References (198)

1. Istvan ES. Structural mechanism for statin inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Am Heart J 144 (6): S27-32 (2002).
2. Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature 343 (6257): 425-30 (1990).
3. Endo A. A historical perspective on the discovery of statins. Proc Jpn Acad Ser B Phys Biol Sci 86 (5): 484-93 (2010).
4. Wolozin B. A fluid connection: cholesterol and Abeta. Proc Natl Acad Sci USA 98 (10): 5371-3 (2001).
5. Doraiswamy PM, Xiong GL. Pharmacological strategies for the prevention of Alzheimer's disease. Expert Opin Pharmacother 7 (1): 1-10 (2006).
6. McGuinness B, O'hare J, Craig D, Bullock R, Malouf R, Passmore P. Statins for the treatment of dementia. Cochrane Database Syst Rev (8): CD007514 (2010).
7. Scott HD, Laake K. Statins for the prevention of Alzheimer's disease. Cochrane Database Syst Rev (4): CD003160 (2001).
8. Kannan M, Steinert JR, Forsythe ID, Smith AG, Chernova T. Mevastatin accelerates loss of synaptic proteins and neurite degeneration in aging cortical neurons in a heme-independent manner. Neurobiol Aging 31 (9): 1543-53 (2010).
9. Mailman T, Hariharan M, Karten B. Inhibition of neuronal cholesterol biosynthesis with lovastatin leads to impaired synaptic vesicle release even in the presence of lipoproteins or geranylgeraniol. J Neurochem 119 (5): 1002-15 (2011).
10. Shrivastava S, Pucadyil TJ, Paila YD, Ganguly S, Chattopadhyay A. Chronic cholesterol depletion using statin impairs the function and dynamics of human serotonin (1A) receptors. Biochemistry 49 (26): 5426-35 (2010).
11. Maggo S, Clark D, Ashton JC. The effect of statins on performance in the Morris water maze in guinea pig. Eur J Pharmacol 674 (2-3): 287-93 (2012).
12. While A, Keen L. The effects of statins on mood: A review of the literature. European journal of cardiovascular nursing: journal of the Working Group on Cardiovascular Nursing of the European Society of Cardiology 11 (1): 85-96 (2012).
13. Liao JK. Statins: potent vascular anti-inflammatory agents. Int J Clin Pract Suppl (143): 41-8 (2004).
14. Shaw SM, Fildes JE, Yonan N, Williams SG. Pleiotropic effects and cholesterol-lowering therapy. Cardiology 112 (1): 4-12 (2009).
15. Pfrieger FW, Ungerer N. Cholesterol metabolism in neurons and astrocytes. Prog Lipid Res 50 (4): 357-71 (2011).
16. Ohvo-Rekila H, Ramstedt B, Leppimaki P, Slotte JP. Cholesterol interactions with phospholipids in membranes. Prog Lipid Res 41 (1): 66-97 (2002).
17. Incardona JP, Eaton S. Cholesterol in signal transduction. Curr Opin Cell Biol 12 (2): 193-203 (2000).
18. Armbrecht HJ, Okuda K, Wongsurawat N, Nemani RK, Chen ML, Boltz MA. Characterization and regulation of the vitamin D hydroxylases. J Steroid Biochem Mol Biol 43 (8): 1073-81 (1992).
19. Hanukoglu I. Steroidogenic enzymes: structure, function, and role in regulation of steroid hormone biosynthesis. J Steroid Biochem Mol Biol 43 (8): 779-804 (1992).
20. Sharpe LJ, Brown AJ. Controlling cholesterol synthesis beyond 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). J Biol Chem 288 (26): 18707-15 (2013).
21. Friesen JA, Rodwell VW. The 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductases. Genome Biol 5 (11): 248 (2004).
22. Edwards PA, Ericsson J. Sterols and isoprenoids: signaling molecules derived from the cholesterol biosynthetic pathway. Annu Rev Biochem 68: 157-85 (1999).
23. Fukada Y, Takao T, Ohguro H, Yoshizawa T, Akino T, Shimonishi Y. Farnesylated gamma-subunit of photoreceptor G protein indispensable for GTP-binding. Nature 346 (6285): 658-60 (1990).
24. Zhang FL, Casey PJ. Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem 65: 241-69 (1996).
25. Ostrowski SM, Wilkinson BL, Golde TE, Landreth G. Statins reduce amyloid-beta production through inhibition of protein isoprenylation. J Biol Chem 282 (37): 26832-44 (2007).
26. Maeda A, Yano T, Itoh Y, Kakumori M, Kubota T, Egashira N, et al. Down-regulation of RhoA is involved in the cytotoxic action of lipophilic statins in HepG2 cells. Atherosclerosis 208 (1): 112-8 (2010).
27. Cohen DE. Balancing cholesterol synthesis and absorption in the gastrointestinal tract. J Clin Lipidol 2 (2): S1-3 (2008).
28. Brown MS, Goldstein JL. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89 (3): 331-40 (1997).
29. Fernandez ML, Mcnamara DJ. Regulation of cholesterol and lipoprotein metabolism in guinea pigs mediated by dietary fat quality and quantity. J Nutr 121 (7): 934-43 (1991).
30. Clarke PR, Hardie DG. Regulation of HMG-CoA reductase: identification of the site phosphorylated by the AMP-activated protein kinase in vitro and in intact rat liver. EMBO J 9 (8): 2439-46 (1990).
31. Hardie DG. Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinology 144 (12): 5179-83 (2003).
32. Horton JD, Shah NA, Warrington JA, Anderson NN, Park SW, Brown MS, et al. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci USA 100 (21): 12027-32 (2003).
33. Jo Y, Debose-Boyd RA. Control of cholesterol synthesis through regulated ER-associated degradation of HMG CoA reductase. Crit Rev Biochem Mol Biol 45 (3): 185-98 (2010).
34. Radhakrishnan A, Sun LP, Kwon HJ, Brown MS, Goldstein JL. Direct binding of cholesterol to the purified membrane region of SCAP: mechanism for a sterol-sensing domain. Mol Cell 15 (2): 259-68 (2004).
35. Yang T, Espenshade PJ, Wright ME, Yabe D, Gong Y, Aebersold R, et al. Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 110 (4): 489-500 (2002).
36. Adams CM, Reitz J, De Brabander JK, Feramisco JD, Li L, Brown MS, et al. Cholesterol and 25-hydroxycholesterol inhibit activation of SREBPs by different mechanisms, both involving SCAP and Insigs. J Biol Chem 279 (50): 52772-80 (2004).
37. Espenshade PJ, Li WP, Yabe D. Sterols block binding of COPII proteins to SCAP, thereby controlling SCAP sorting in ER. Proc Natl Acad Sci USA 99 (18): 11694-9 (2002).
38. Duncan EA, Brown MS, Goldstein JL, Sakai J. Cleavage site for sterol-regulated protease localized to a leu-Ser bond in the lumenal loop of sterol regulatory element-binding protein-2. J Biol Chem 272 (19): 12778-85 (1997).
39. Duncan EA, Dave UP, Sakai J, Goldstein JL, Brown MS. Secondsite cleavage in sterol regulatory element-binding protein occurs at transmembrane junction as determined by cysteine panning. J Biol Chem 273 (28): 17801-9 (1998).
40. Brown MS, Goldstein JL. A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc Natl Acad Sci USA 96 (20): 11041-8 (1999).
41. Sever N, Yang T, Brown MS, Goldstein JL, Debose-Boyd RA. Accelerated degradation of HMG CoA reductase mediated by binding of insig-1 to its sterol-sensing domain. Mol Cell 11 (1): 25-33 (2003).
42. Faust JR, Luskey KL, Chin DJ, Goldstein JL, Brown MS. Regulation of synthesis and degradation of 3-hydroxy-3-methylglutarylcoenzyme A reductase by low density lipoprotein and 25-hydroxycholesterol in UT-1 cells. Proc Natl Acad Sci USA 79 (17): 5205-9 (1982).
43. Edwards PA, Lan SF, Fogelman AM. Alterations in the rates of synthesis and degradation of rat liver 3-hydroxy-3-methylglutaryl coenzyme A reductase produced by cholestyramine and mevinolin. J Biol Chem 258 (17): 10219-22 (1983).
44. Nakanishi M, Goldstein JL, Brown MS. Multivalent control of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Mevalonatederived product inhibits translation of mRNA and accelerates degradation of enzyme. J Biol Chem 263 (18): 8929-37 (1988).
45. Song BL, Sever N, Debose-Boyd RA. Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterolregulated ubiquitination to degradation of HMG CoA reductase. Mol Cell 19 (6): 829-40 (2005).
46. Endo A, Kuroda M, Tanzawa K. Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity. FEBS Lett 72 (2): 323-6 (1976).
47. Fda. Consumer Health Information,. (2010).
48. Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol 19 (1): 117-25 (2005).
49. Botti RE, Triscari J, Pan HY, Zayat J. Concentrations of pravastatin and lovastatin in cerebrospinal fluid in healthy subjects. Clin Neuropharmacol 14 (3): 256-61 (1991).
50. Gruer PJ, Vega JM, Mercuri MF, Dobrinska MR, Tobert JA. Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin. Am J Cardiol 84 (7): 811-5 (1999).
51. Hatanaka T. Clinical pharmacokinetics of pravastatin: mechanisms of pharmacokinetic events. Clin Pharmacokinet 39 (6): 397-412 (2000).
52. Hyyppa MT, Kronholm E, Virtanen A, Leino A, Jula A. Does simvastatin affect mood and steroid hormone levels in hypercholesterolemic men? A randomized double-blind trial. Psychoneuroendocrinol 28 (2): 181-94 (2003).
53. Tuccori M, Montagnani S, Mantarro S, Capogrosso-Sansone A, Ruggiero E, Saporiti A, et al. Neuropsychiatric Adverse Events Associated with Statins: Epidemiology, Pathophysiology, Prevention and Management. CNS Drugs 28 (3): 249-72 (2014).
54. Zhou Q, Liao JK. Pleiotropic effects of statins. -Basic research and clinical perspectives. Circ J 74 (5): 818-26 (2010).
55. Schonbeck U, Libby P. Inflammation, immunity, and HMG-CoA reductase inhibitors: statins as antiinflammatory agents? Circulation 109 (21 Suppl 1): II18-26 (2004).
56. Phillip Owens A, III, Mackman N. The antithrombotic effects of statins. Annu Rev Med 65: 433-45 (2014).
57. Dietschy JM, Turley SD. Cholesterol metabolism in the brain. Curr Opin Lipidol 12 (2): 105-12 (2001).
58. Mauch DH, Nagler K, Schumacher S, Goritz C, Muller EC, Otto A, et al. CNS synaptogenesis promoted by glia-derived cholesterol. Science (New York, NY) 294 (5545): 1354-7 (2001).
59. Pfrieger FW. Role of cholesterol in synapse formation and function. Biochimica et biophysica acta 1610 (2): 271-80 (2003).
60. McConihay JA, Horn PS, Woollett LA. Effect of maternal hypercholesterolemia on fetal sterol metabolism in the Golden Syrian hamster. J Lipid Res 42 (7): 1111-9 (2001).
61. Bertossi M, Virgintino D, Errede M, Roncali L. Immunohistochemical and ultrastructural characterization of cortical plate microvasculature in the human fetus telencephalon. Microvasc Res 58 (1): 49-61 (1999).
62. Pitas RE, Boyles JK, Lee SH, Hui D, Weisgraber KH. 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. J Biol Chem 262 (29): 14352-60 (1987).
63. Nieweg K, Schaller H, Pfrieger FW. Marked differences in cholesterol synthesis between neurons and glial cells from postnatal rats. J Neurochem 109 (1): 125-34 (2009).
64. Dietschy JM, Turley SD. Thematic review series: brain Lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res 45 (8): 1375-97 (2004).
65. Poirier J, Baccichet A, Dea D, Gauthier S. Cholesterol synthesis and lipoprotein reuptake during synaptic remodelling in hippocampus in adult rats. Neuroscience 55 (1): 81-90 (1993).
66. Pfrieger FW. Outsourcing in the brain: do neurons depend on cholesterol delivery by astrocytes? Bioessays 25 (1): 72-8 (2003).
67. Hayashi H. Lipid metabolism and glial lipoproteins in the central nervous system. Biol Pharm Bull 34 (4): 453-61 (2011).
68. Boyles JK, Pitas RE, Wilson E, Mahley RW, Taylor JM. Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system. J Clin Invest 76 (4): 1501-13 (1985).
69. Vance JE, Hayashi H. Formation and function of apolipoprotein Econtaining lipoproteins in the nervous system. Biochimica et biophysica acta 1801 (8): 806-18 (2010).
70. Fukumoto H, Deng A, Irizarry MC, Fitzgerald ML, Rebeck GW. Induction of the cholesterol transporter ABCA1 in central nervous system cells by liver X receptor agonists increases secreted Abeta levels. J Biol Chem 277 (50): 48508-13 (2002).
71. Wellington CL, Walker EK, Suarez A, Kwok A, Bissada N, Singaraja R, et al. ABCA1 mRNA and protein distribution patterns predict multiple different roles and levels of regulation. Lab Invest 82 (3): 273-83 (2002).
72. Bjorkhem I, Meaney S. Brain cholesterol: long secret life behind a barrier. Arteriosclerosis, thrombosis, Vasc Biol 24 (5): 806-15 (2004).
73. Ong WY, Hu CY, Soh YP, Lim TM, Pentchev PG, Patel SC. Neuronal localization of sterol regulatory element binding protein-1 in the rodent and primate brain: a light and electron microscopic immunocytochemical study. Neuroscience 97 (1): 143-53 (2000).
74. Vance JE, Pan D, Campenot RB, Bussiere M, Vance DE. Evidence that the major membrane lipids, except cholesterol, are made in axons of cultured rat sympathetic neurons. J Neurochem 62 (1): 329-37 (1994).
75. Matsuda A, Nagao K, Matsuo M, Kioka N, Ueda K. 24 (S)-hydroxycholesterol is actively eliminated from neuronal cells by ABCA1. J Neurochem 126 (1): 93-101 (2013).
76. Bretillon L, Diczfalusy U, Bjorkhem I, Maire MA, Martine L, Joffre C, et al. Cholesterol-24S-hydroxylase (CYP46A1) is specifically expressed in neurons of the neural retina. Curr Eye Res 32 (4): 361-6 (2007).
77. Gosselet F, Saint-Pol J, Fenart L. Effects of oxysterols on the blood-brain barrier: Implications for Alzheimer's disease. Biochem Biophys Res Commun 446 (3): 687-91 (2014).
78. Leoni V, Masterman T, Patel P, Meaney S, Diczfalusy U, Bjorkhem I. Side chain oxidized oxysterols in cerebrospinal fluid and the integrity of blood-brain and blood-cerebrospinal fluid barriers. J Lipid Res 44 (4): 793-9 (2003).
79. Heverin M, Bogdanovic N, Lutjohann D, Bayer T, Pikuleva I, Bretillon L, et al. Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease. J Lipid Res 45 (1): 186-93 (2004).
80. Shafaati M, Marutle A, Pettersson H, Lovgren-Sandblom A, Olin M, Pikuleva I, et al. Marked accumulation of 27-hydroxycholesterol in the brains of Alzheimer's patients with the Swedish APP 670/671 mutation. J Lipid Res 52 (5): 1004-10 (2011).
81. Ledesma MD, Dotti CG. Peripheral cholesterol, metabolic disorders and Alzheimer's disease. Frontiers in bioscience 4: 181-94 (2012).
82. Kalaria RN. Small vessel disease and Alzheimer's dementia: pathological considerations. Cerebrovasc Dis 13 (l2): 48-52 (2002).
83. Jarvik GP, Austin MA, Fabsitz RR, Auwerx J, Reed T, Christian JC, et al. Genetic influences on age-related change in total cholesterol, low density lipoprotein-cholesterol, and triglyceride levels: longitudinal apolipoprotein E genotype effects. Genetic epidemiology 11 (4): 375-84 (1994).
84. Gomez-Isla T, West HL, Rebeck GW, Harr SD, Growdon JH, Locascio JJ, et al. Clinical and pathological correlates of apolipoprotein E epsilon 4 in Alzheimer's disease. Ann Neurol 39 (1): 62-70 (1996).
85. Notkola IL, Sulkava R, Pekkanen J, Erkinjuntti T, Ehnholm C, Kivinen P, et al. Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease. Neuroepidemiology 17 (1): 14-20 (1998).
86. Solomon A, Kivipelto M, Wolozin B, Zhou J, Whitmer RA. Midlife serum cholesterol and increased risk of Alzheimer's and vascular dementia three decades later. Dement Geriatr Cogn Disord 28 (1): 75-80 (2009).
87. Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet 41 (10): 1088-93 (2009).
88. Seshadri S, Fitzpatrick AL, Ikram MA, Destefano AL, Gudnason V, Boada M, et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 303 (18): 1832-40 (2010).
89. Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, Buros J, et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet 43 (5): 436-41 (2011).
90. Bretillon L, Siden A, Wahlund LO, Lutjohann D, Minthon L, Crisby M, et al. Plasma levels of 24S-hydroxycholesterol in patients with neurological diseases. Neurosci Lett 293 (2): 87-90 (2000).
91. Papassotiropoulos A LD, Bagli M, Locatelli S, Jessen F, Rao ML, Maier W, et al. Plasma 24S-hydroxycholesterol: a peripheral indicator of neuronal degeneration and potential state marker for Alzheimer's disease. Neuroreport 11 (9): 1959-62 (2000).
92. 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 41 (2): 195-8 (2000).
93. Hughes TM, Rosano C, Evans RW, Kuller LH. Brain cholesterol metabolism, oxysterols, and dementia. J Alzheimers Dis 33 (4): 891-911 (2013).
94. Shobab LA, Hsiung GY, Feldman HH. Cholesterol in Alzheimer's disease. Lancet neurology 4 (12): 841-52 (2005).
95. Sparks DL, Scheff SW, Hunsaker JC, III, Liu H, Landers T, Gross DR. Induction of Alzheimer-like beta-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol. Exp Neurol 126 (1): 88-94 (1994).
96. Sparks DL, Kuo YM, Roher A, Martin T, Lukas RJ. Alterations of Alzheimer's disease in the cholesterol-fed rabbit, including vascular inflammation. Preliminary observations. Ann N Y Acad Sci 903 335-44 (2000).
97. Refolo LM, Malester B, Lafrancois J, Bryant-Thomas T, Wang R, Tint GS, et al. Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol Dis 7 (4): 321-31 (2000).
98. Shie FS, Jin LW, Cook DG, Leverenz JB, Leboeuf RC. Dietinduced hypercholesterolemia enhances brain A beta accumulation in transgenic mice. Neuroreport 13 (4): 455-9 (2002).
99. Simons M, Keller P, De Strooper B, Beyreuther K, Dotti CG, Simons K. Cholesterol depletion inhibits the generation of betaamyloid in hippocampal neurons. Proc Natl Acad Sci USA 95 (11): 6460-4 (1998).
100. Kalvodova. Lipids as modulators of proteolytic activity of BACE: involvement of cholesterol, glycosphingolipids, and anionic phospholipids in vitro. J Biol Chem 280 (44): 36815-23 (2005).
101. Ghribi O, Golovko MY, Larsen B, Schrag M, Murphy EJ. Deposition of iron and beta-amyloid plaques is associated with cortical cellular damage in rabbits fed with long-term cholesterol-enriched diets. J Neurochem 99 (2): 438-49 (2006).
102. Kalvodova L, Kahya N, Schwille P, Ehehalt R, Verkade P, Drechsel D, et al. Lipids as modulators of proteolytic activity of BACE: involvement of cholesterol, glycosphingolipids, and anionic phospholipids in vitro. J Biol Chem 280 (44): 36815-23 (2005).
103. Hughes TM, Lopez OL, Evans RW, Kamboh MI, Williamson JD, Klunk WE, et al. Markers of cholesterol transport are associated with amyloid deposition in the brain. Neurobiol Aging 35 (4): 802-7 (2013).
104. Mendoza-Oliva A, Ferrera P, Arias C. Interplay between cholesterol and homocysteine in the exacerbation of amyloid-beta toxicity in human neuroblastoma cells. CNS Neurol Disord Drug Targets 12 (6): 842-8 (2013).
105. Ferrera P, Mercado-Gomez O, Silva-Aguilar M, Valverde M, Arias C. Cholesterol potentiates beta-amyloid-induced toxicity in human neuroblastoma cells: involvement of oxidative stress. Neurochem Res 33 (8): 1509-17 (2008).
106. Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet 356 (9242): 1627-31 (2000).
107. Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol 57 (10): 1439-43 (2000).
108. Kurata T, Kawai H, Miyazaki K, Kozuki M, Morimoto N, Ohta Y, et al. Statins have therapeutic potential for the treatment of Alzheimer's disease, likely via protection of the neurovascular unit in the AD brain. J Neurol Sci 322 (1-2): 59-63 (2012).
109. Butterfield DA, Barone E, Mancuso C. Cholesterol-independent neuroprotective and neurotoxic activities of statins: perspectives for statin use in Alzheimer disease and other age-related neurodegenerative disorders. Pharmacological research: the official journal of the Italian Pharmacological Society 64 (3): 180-6 (2011).
110. Simons M, Schwarzler F, Lutjohann D, Von Bergmann K, Beyreuther K, Dichgans J, et al. Treatment with simvastatin in normocholesterolemic patients with Alzheimer's disease: A 26-week randomized, placebo-controlled, double-blind trial. Ann Neurol 52 (3): 346-50 (2002).
111. Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann D, Keller P, et al. 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 (10): 5856-61 (2001).
112. Lutjohann D, Stroick M, Bertsch T, Kuhl S, Lindenthal B, Thelen K, et al. High doses of simvastatin, pravastatin, and cholesterol reduce brain cholesterol synthesis in guinea pigs. Steroids 69 (6): 431-8 (2004).
113. Cole SL, Grudzien A, Manhart IO, Kelly BL, Oakley H, Vassar R. Statins cause intracellular accumulation of amyloid precursor protein, beta-secretase-cleaved fragments, and amyloid beta-peptidevia an isoprenoid-dependent mechanism. J Biol Chem 280 (19): 18755-70 (2005).
114. Vega GL, Weiner MF, Lipton AM, Von Bergmann K, Lutjohann D, Moore C, et al. Reduction in levels of 24S-hydroxycholesterol by statin treatment in patients with Alzheimer disease. Archives of neurology 60 (4): 510-5 (2003).
115. Eckert GP, Kirsch C, Mueller WE. Differential effects of lovastatin treatment on brain cholesterol levels in normal and apoE-deficient mice. Neuroreport 12 (5): 883-7 (2001).
116. Kirsch C, Eckert GP, Mueller WE. Statin effects on cholesterol micro-domains in brain plasma membranes. Biochemical pharmacology 65 (5): 843-56 (2003).
117. Thelen KM, Rentsch KM, Gutteck U, Heverin M, Olin M, Andersson U, et al. Brain cholesterol synthesis in mice is affected by high dose of simvastatin but not of pravastatin. J Pharmacol Exp Ther 316 (3): 1146-52 (2006).
118. Naidu A, Xu Q, Catalano R, Cordell B. Secretion of apolipoprotein E by brain glia requires protein prenylation and is suppressed by statins. Brain Res 958 (1): 100-11 (2002).
119. Johnson-Anuna LN, Eckert GP, Keller JH, Igbavboa U, Franke C, Fechner T, et al. Chronic administration of statins alters multiple gene expression patterns in mouse cerebral cortex. J Pharmacol Exp Ther 312 (2): 786-93 (2005).
120. Van Der Most PJ, Dolga AM, Nijholt IM, Luiten PG, Eisel UL. Statins: mechanisms of neuroprotection. Prog Neurobiol 88 (1): 64-75 (2009).
121. Barone E, Cenini G, Di Domenico F, Martin S, Sultana R, Mancuso C, et al. Long-term high-dose atorvastatin decreases brain oxidative and nitrosative stress in a preclinical model of Alzheimer disease: a novel mechanism of action. Pharmacol Res 63 (3): 172-80 (2011).
122. Parsons RB, Price GC, Farrant JK, Subramaniam D, Adeagbo-Sheikh J, Austen BM. Statins inhibit the dimerization of betasecretase via both isoprenoid-and cholesterol-mediated mechanisms. Biochem J 399 (2): 205-14 (2006).
123. Murphy MP, Morales J, Beckett TL, Astarita G, Piomelli D, Weidner A, et al. Changes in cognition and amyloid-beta processing with long term cholesterol reduction using atorvastatin in aged dogs. J Alzheimers Dis 22 (1): 135-50 (2010).
124. Hoglund K, Thelen KM, Syversen S, Sjogren M, Von Bergmann K, Wallin A, et al. The effect of simvastatin treatment on the amyloid precursor protein and brain cholesterol metabolism in patients with Alzheimer's disease. Dement Geriatr Cogn Disord 19 (5-6): 256-65 (2005).
125. Kojro E, Fuger P, Prinzen C, Kanarek AM, Rat D, Endres K, et al. Statins and the squalene synthase inhibitor zaragozic acid stimulate the non-amyloidogenic pathway of amyloid-beta protein precursor processing by suppression of cholesterol synthesis. J Alzheimers Dis 20 (4): 1215-31 (2010).
126. Tamboli IY, Barth E, Christian L, Siepmann M, Kumar S, Singh S, et al. Statins promote the degradation of extracellular amyloid {beta}-peptide by microglia via stimulation of exosome-associated insulin-degrading enzyme (IDE) secretion. J Biol Chem 285 (48): 37405-14 (2010).
127. Won JS, Im YB, Khan M, Contreras M, Singh AK, Singh I. Lovastatin inhibits amyloid precursor protein (APP) beta-cleavage through reduction of APP distribution in Lubrol WX extractable low density lipid rafts. J Neurochem 105 (4): 1536-49 (2008).
128. Hosaka A, Araki W, Oda A, Tomidokoro Y, Tamaoka A. Statins reduce amyloid beta-peptide production by modulating amyloid precursor protein maturation and phosphorylation through a cholesterol-independent mechanism in cultured neurons. Neurochem Res 38 (3): 589-600 (2013).
129. Salins P, Shawesh S, He Y, Dibrov A, Kashour T, Arthur G, et al. Lovastatin protects human neurons against Abeta-induced toxicity and causes activation of beta-catenin-TCF/LEF signaling. Neurosci Lett 412 (3): 211-6 (2007).
130. Rubio-Perez JM, Morillas-Ruiz JM. A review: inflammatory process in Alzheimer's disease, role of cytokines. TheScientificWorld-Journal 2012 756357 (2012).
131. Kurata T, Miyazaki K, Kozuki M, Morimoto N, Ohta Y, Ikeda Y, et al. Atorvastatin and pitavastatin reduce senile plaques and inflammatory responses in a mouse model of Alzheimer's disease. Neurol Res 34 (6): 601-10 (2012).
132. Kurata T, Miyazaki K, Kozuki M, Panin VL, Morimoto N, Ohta Y, et al. Atorvastatin and pitavastatin improve cognitive function and reduce senile plaque and phosphorylated tau in aged APP mice. Brain Res 1371: 161-70 (2011).
133. Zhang YY, Fan YC, Wang M, Wang D, Li XH. Atorvastatin attenuates the production of IL-1beta, IL-6, and TNF-alpha in the hippocampus of an amyloid beta1-42-induced rat model of Alzheimer's disease. Clin Interv Aging 8: 103-10 (2013).
134. Tong XK, Nicolakakis N, Fernandes P, Ongali B, Brouillette J, Quirion R, et al. Simvastatin improves cerebrovascular function and counters soluble amyloid-beta, inflammation and oxidative stress in aged APP mice. Neurobiol Dis 35 (3): 406-14 (2009).
135. Cordle A, Landreth G. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors attenuate beta-amyloid-induced microglial inflammatory responses. J Neurosci 25 (2): 299-307 (2005).
136. Bi X, Baudry M, Liu J, Yao Y, Fu L, Brucher F, et al. Inhibition of geranylgeranylation mediates the effects of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors on microglia. J Biol Chem 12279 (46): 48238-45 (2004).
137. Zhu X, Su B, Wang X, Smith MA, Perry G. Causes of oxidative stress in Alzheimer disease. Cellular and molecular life sciences: CMLS 64 (17): 2202-10 (2007).
138. Sultana R, Butterfield DA. Role of oxidative stress in the progression of Alzheimer's disease. J Alzheimers Dis 19 (1): 341-53 (2010).
139. Tramontina AC, Wartchow KM, Rodrigues L, Biasibetti R, Quincozes-Santos A, Bobermin L, et al.The neuroprotective effect of two statins: simvastatin and pravastatin on a streptozotocininduced model of Alzheimer's disease in rats. J Neural Transm (Vienna, Austria: 1996) 118 (11): 1641-9 (2011).
140. Kurata T, Miyazaki K, Morimoto N, Kawai H, Ohta Y, Ikeda Y, et al. Atorvastatin and pitavastatin reduce oxidative stress and improve IR/LDL-R signals in Alzheimer's disease. Neurol Res 35 (2): 193-205 (2013).
141. Kurinami H, Sato N, Shinohara M, Takeuchi D, Takeda S, Shimamura M, et al. Prevention of amyloid beta-induced memory impairment by fluvastatin, associated with the decrease in amyloid beta accumulation and oxidative stress in amyloid beta injection mouse model. Intern J Mol Med 21 (5): 531-7 (2008).
142. Mattson MP. Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders. Neuromol Med 3 (2): 65-94 (2003).
143. Zacco A, Togo J, Spence K, Ellis A, Lloyd D, Furlong S, et al. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors protect cortical neurons from excitotoxicity. J Neurosci 23 (35): 11104-11 (2003).
144. Bosel J, Gandor F, Harms C, Synowitz M, Harms U, Djoufack PC, et al. Neuroprotective effects of atorvastatin against glutamateinduced excitotoxicity in primary cortical neurones. J Neurochem 92 (6): 1386-98 (2005).
145. Ponce J, De La Ossa NP, Hurtado O, Millan M, Arenillas JF, Davalos A, et al. Simvastatin reduces the association of NMDA receptors to lipid rafts: a cholesterol-mediated effect in neuroprotection. Stroke 39 (4): 1269-75 (2008).
146. Dolga AM, Nijholt IM, Ostroveanu A, Ten Bosch Q, Luiten PG, Eisel UL. Lovastatin induces neuroprotection through tumor necrosis factor receptor 2 signaling pathways. J Alzheimers Dis 13 (2): 111-22 (2008).
147. Farooqui AA, Horrocks LA. Phospholipase A2-generated lipid mediators in the brain: the good, the bad, and the ugly. The Neuroscientist: a review journal bringing neurobiology, neurology and psychiatry 12 (3): 245-60 (2006).
148. Aihara M, Ishii S, Kume K, Shimizu T. Interaction between neurone and microglia mediated by platelet-activating factor. Genes to cells: devoted to molecular & cellular mechanisms 5 (5): 397-406 (2000).
149. Bate C, Kempster S, Williams A. Platelet-activating factor antagonists protect amyloid-beta damaged neurons from microgliamediated death. Neuropharmacology 51 (2): 173-81 (2006).
150. Bate C, Tayebi M, Williams A. Ginkgolides protect against amyloid-beta1-42-mediated synapse damage in vitro. Mol Neurodegener 3: 1 (2008)
151. Bate C, Rumbold L, Williams A. Cholesterol synthesis inhibitors protect against platelet-activating factor-induced neuronal damage. J Neuroinflammation 4: 5 (2007).
152. Evangelopoulos ME, Weis J, Kruttgen A. Mevastatin-induced neurite outgrowth of neuroblastoma cells via activation of EGFR. J Neurosci Res 87 (9): 2138-44 (2009).
153. Fernandez-Hernando C, Suarez Y, Lasuncion MA. Lovastatininduced PC-12 cell differentiation is associated with RhoA/RhoA kinase pathway inactivation. Mol Cell Neurosci 29 (4): 591-602 (2005).
154. Pooler AM, Xi SC, Wurtman RJ. The 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitor pravastatin enhances neurite outgrowth in hippocampal neurons. J Neurochem 97 (3): 716-23 (2006).
155. Jin Y, Sui HJ, Dong Y, Ding Q, Qu WH, Yu SX, et al. Atorvastatin enhances neurite outgrowth in cortical neurons in vitro via upregulating the Akt/mTOR and Akt/GSK-3beta signaling pathways. Acta pharmacologica Sinica 33 (7): 861-72 (2012).
156. Posada-Duque RA, Velasquez-Carvajal D, Eckert GP, Cardona-Gomez GP. Atorvastatin requires geranylgeranyl transferase-I and Rac1 activation to exert neuronal protection and induce plasticity. Neurochem Intern 62 (4): 433-45 (2013).
157. Wang H, Lynch JR, Song P, Yang HJ, Yates RB, Mace B, et al. Simvastatin and atorvastatin improve behavioral outcome, reduce hippocampal degeneration, and improve cerebral blood flow after experimental traumatic brain injury. Exp Neurol 206 (1): 59-69 (2007).
158. Lu D, Qu C, Goussev A, Jiang H, Lu C, Schallert T, et al. Statins increase neurogenesis in the dentate gyrus, reduce delayed neuronal death in the hippocampal CA3 region, and improve spatial learning in rat after traumatic brain injury. J Neurotrauma 24 (7): 1132-46 (2007).
159. Tanaka N, Katayama Y, Katsumata T, Otori T, Nishiyama Y. Effects of long-term administration of HMG-CoA reductase inhibitor, atorvastatin, on stroke events and local cerebral blood flow in stroke-prone spontaneously hypertensive rats. Brain Res 1169: 125-32 (2007).
160. Chen J, Zhang ZG, Li Y, Wang Y, Wang L, Jiang H, et al. Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann Neurol 53 (6): 743-51 (2003).
161. Chen J, Zhang C, Jiang H, Li Y, Zhang L, Robin A, et al. Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice. J Cereb Blood Flow Metab 25 (2): 281-90 (2005).
162. Pavlov OV, Bobryshev Yu V, Balabanov Yu V, Ashwell K. An in vitro study of the effects of lovastatin on human fetal brain cells. Neurotoxicol Teratol 17 (1): 31-9 (1995).
163. Michikawa M, Yanagisawa K. Inhibition of cholesterol production but not of nonsterol isoprenoid products induces neuronal cell death. J Neurochem 72 (6): 2278-85 (1999).
164. Kumar B, Andreatta C, Koustas WT, Cole WC, Edwards-Prasad J, Prasad KN. Mevastatin induces degeneration and decreases viability of cAMP-induced differentiated neuroblastoma cells in culture by inhibiting proteasome activity, and mevalonic acid lactone prevents these effects. J Neurosci Res 68 (5): 627-35 (2002).
165. Arnold DE, Gagne C, Niknejad N, Mcburney MW, Dimitroulakos J. Lovastatin induces neuronal differentiation and apoptosis of embryonal carcinoma and neuroblastoma cells: enhanced differentiation and apoptosis in combination with dbcAMP. Mol Cell Biochem 345 (1-2): 1-11 (2010).
166. Marcuzzi A, Tricarico PM, Piscianz E, Kleiner G, Vecchi Brumatti L, Crovella S. Lovastatin induces apoptosis through the mitochondrial pathway in an undifferentiated SH-SY5Y neuroblastoma cell line. Cell death & disease 4: e585 (2013).
167. Lane KT, Beese LS. Thematic review series: lipid posttranslational modifications. Structural biology of protein farnesyltransferase and geranylgeranyltransferase type I. J Lipid Res 47 (4): 681-99 (2006).
168. Jaffe AB, Hall A. Rho GTPases: biochemistry and biology. Annual review of cell and developmental biology 21: 247-69 (2005).
169. Murakoshi H, Wang H, Yasuda R. Local, persistent activation of Rho GTPases during plasticity of single dendritic spines. Nature 472 (7341): 100-4 (2011).
170. Martino A, Ettorre M, Musilli M, Lorenzetto E, Buffelli M, Diana G. Rho GTPase-dependent plasticity of dendritic spines in the adult brain. Front Cell Neurosci 7: 62 (2013).
171. Hooff GP, Peters I, Wood WG, Muller WE, Eckert GP. Modulation of cholesterol, farnesylpyrophosphate, and geranylgeranylpyrophosphate in neuroblastoma SH-SY5Y-APP695 cells: impact on amyloid beta-protein production. Mol Neurobiol 41 (2-3): 341-50 (2010).
172. Eckert GP, Hooff GP, Strandjord DM, Igbavboa U, Volmer DA, Muller WE, et al. Regulation of the brain isoprenoids farnesyl-and geranylgeranylpyrophosphate is altered in male Alzheimer patients. Neurobiol Dis 35 (2): 251-7 (2009).
173. Vural K, Tuglu MI. Neurotoxic effect of statins on mouse neuroblastoma NB2a cell line. Eur Rev Med Pharmacol Sci 15 (9): 985-91 (2011).
174. Schulz JG, Bosel J, Stoeckel M, Megow D, Dirnagl U, Endres M. HMG-CoA reductase inhibition causes neurite loss by interfering with geranylgeranylpyrophosphate synthesis. J Neurochem 89 (1): 24-32 (2004).
175. Tanaka T, Tatsuno I, Uchida D, Moroo I, Morio H, Nakamura S, et al. Geranylgeranyl-pyrophosphate, an isoprenoid of mevalonate cascade, is a critical compound for rat primary cultured cortical neurons to protect the cell death induced by 3-hydroxy-3-methylglutaryl-CoA reductase inhibition. J Neurosci 20 (8): 2852-9 (2000).
176. Meske V, Albert F, Richter D, Schwarze J, Ohm TG. Blockade of HMG-CoA reductase activity causes changes in microtubulestabilizing protein tau via suppression of geranylgeranylpyrophosphate formation: implications for Alzheimer's disease. Eur J Neurosci 17 (1): 93-102 (2003).
177. Fan QW, Yu W, Senda T, Yanagisawa K, Michikawa M. Cholesterol-dependent modulation of tau phosphorylation in cultured neurons. J Neurochem 76 (2): 391-400 (2001).
178. Padala KP, Padala PR, Potter JF. Simvastatin-induced decline in cognition. Ann Pharmacother 40 (10): 1880-3 (2006).
179. Evans MA, Golomb BA. Statin-associated adverse cognitive effects: survey results from 171 patients. Pharmacotherapy 29 (7): 800-11 (2009).
180. Fda. FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs (2012).
181. You H, Lu W, Zhao S, Hu Z, Zhang J. The relationship between statins and depression: a review of the literature. Expert Opin Pharmacother 14 (11): 1467-76 (2013).
182. Hawes CM, Wiemer H, Krueger SR, Karten B. Pre-synaptic defects of NPC1-deficient hippocampal neurons are not directly related to plasma membrane cholesterol. J Neurochem 114 (1): 311-22 (2010).
183. Linetti A, Fratangeli A, Taverna E, Valnegri P, Francolini M, Cappello V, et al. Cholesterol reduction impairs exocytosis of synaptic vesicles. J Cell Sci 123 (Pt 4): 595-605 (2010).
184. Wasser CR, Ertunc M, Liu X, Kavalali ET. Cholesterol-dependent balance between evoked and spontaneous synaptic vesicle recycling. J Physiol 579 (Pt 2): 413-29 (2007).
185. Koudinov AR, Koudinova NV. Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J 15 (10): 1858-60 (2001).
186. Matthies H, Jr., Schulz S, Hollt V, Krug M. Inhibition by compactin demonstrates a requirement of isoprenoid metabolism for long-term potentiation in rat hippocampal slices. Neuroscience 79 (2): 341-6 (1997).
187. Tong J, Borbat PP, Freed JH, Shin YK. A scissors mechanism for stimulation of SNARE-mediated lipid mixing by cholesterol. Proc Natl Acad Sci USA 106 (13): 5141-6 (2009).
188. Shin Y. Cholesterol, Statins, and Brain Function: A Hypothesis from a Molecular Perspective. IBC 1 (2009).
189. Schilling JM, Cui W, Godoy JC, Risbrough VB, Niesman IR, Roth DM, et al. Long-term atorvastatin treatment leads to alterations in behavior, cognition, and hippocampal biochemistry. Behavioural Brain Res 267: 6-11 (2014).
190. Hering H, Lin CC, Sheng M. Lipid rafts in the maintenance of synapses, dendritic spines, and surface AMPA receptor stability. J Neurosci 23 (8): 3262-71 (2003).
191. Soto-Hernández KA, Loza Escutia O, García Mendoza N. Estatinas en adultos mayores, una población creciente. Rev Facultad de Medicina, UNAM 56 (1): 19-29 (2012).
192. Thelen KM, Falkai P, Bayer TA, Lutjohann D. Cholesterol synthesis rate in human hippocampus declines with aging. Neurosci Lett 403 (1-2): 15-9 (2006).
193. Sparks DL, Lemieux SK, Haut MW, Baxter LC, Johnson SC, Sparks LM, et al. Hippocampal volume change in the Alzheimer Disease Cholesterol-Lowering Treatment trial. Cleve Clin J Med 75 (2): S87-93 (2008).
194. Algotsson A, Winblad B. Patients with Alzheimer's disease may be particularly susceptible to adverse effects of statins. Dement Geriatr Cogn Disord 17 (3): 109-16 (2004).
195. Kelley BJ, Glasser S. Cognitive effects of statin medications. CNS Drugs 28 (5): 411-9 (2014).
196. Parvathy S, Ehrlich M, Pedrini S, Diaz N, Refolo L, Buxbaum JD, et al. Atorvastatin-induced activation of Alzheimer's alpha secretase is resistant to standard inhibitors of protein phosphorylationregulated ectodomain shedding. J Neurochem 90 (4): 1005-10 (2004).
197. Garcia-Roman N, Alvarez AM, Toro MJ, Montes A, Lorenzo MJ. Lovastatin induces apoptosis of spontaneously immortalized rat brain neuroblasts: involvement of nonsterol isoprenoid biosynthesis inhibition. Mol Cell Neurosci 17 (2): 329-41 (2001).
198. Fan QW, Yu W, Gong JS, Zou K, Sawamura N, Senda T, et al. Cholesterol-dependent modulation of dendrite outgrowth and microtubule stability in cultured neurons. J Neurochem 80 (1): 178-90 (2002).