Cholesterol and statins in Alzheimer's disease: Current controversies

Experimental Neurology - Tập 223 - Trang 282-293 - 2010
Ana Catarina R.G. Fonseca1, Rosa Resende1, Catarina R. Oliveira1,2, Cláudia M.F. Pereira1,2
1Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal
2Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-517 Coimbra, Portugal

Tài liệu tham khảo

Abad-Rodriguez, 2004, Neuronal membrane cholesterol loss enhances amyloid peptide generation, J. Cell Biol., 167, 953, 10.1083/jcb.200404149 Akasofu, 2008, Study of neuroprotection of donepezil, a therapy for Alzheimer's disease, Chem.-Biol. Interact., 175, 222, 10.1016/j.cbi.2008.04.045 Arispe, 2002, Plasma membrane cholesterol controls the cytotoxicity of Alzheimer's disease AβP (1–40) and (1–42) peptides, FASEB J., 16, 1526, 10.1096/fj.02-0829com Bate, 2007, Squalestatin protects neurons and reduces the activation of cytoplasmic phospholipase A2 by Aβ1-42, Neuropharmacology, 53, 222, 10.1016/j.neuropharm.2007.05.003 Beeri, 2006, Coronary artery disease is associated with Alzheimer disease neuropathology in APOE4 carriers, Neurology, 66, 1399, 10.1212/01.wnl.0000210447.19748.0b Bi, 2004, Inhibition of geranylgeranylation mediates the effects of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors on microglia, J. Biol. Chem., 279, 48238, 10.1074/jbc.M405442200 Bieschke, 2005, Oxidative metabolites accelerate Alzheimer's amyloidogenesis by a two-step mechanism, eliminating the requirement for nucleation, Biochemistry, 44, 4977, 10.1021/bi0501030 Blanco-Colio, 2002, 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors, atorvastatin and simvastatin, induce apoptosis of vascular smooth muscle cells by downregulation of Bcl-2 expression and Rho A prenylation, Atherosclerosis, 161, 17, 10.1016/S0021-9150(01)00613-X Bodovitz, 1996, Cholesterol modulates α-secretase cleavage of amyloid precursor protein, J. Biol. Chem., 271, 4436, 10.1074/jbc.271.8.4436 Borronia, 2004, Intronic CYP46 polymorphism along with ApoE genotype in sporadic Alzheimer disease: from risk factors to disease modulators, Neurobiol. Aging, 25, 747, 10.1016/j.neurobiolaging.2003.08.004 Bösel, 2005, Neuroprotective effects of atorvastatin against glutamate-induced excitotoxicity in primary cortical neurones, J. Neurochem., 92, 1386, 10.1111/j.1471-4159.2004.02980.x Burns, 2003, Use of in vivo models to study the role of cholesterol in the etiology of Alzheimer's disease, Neurochem. Res., 21, 979, 10.1023/A:1023294820218 Burns, 2003, Presenilin redistribution associated with aberrant cholesterol transport enhances β-amyloid production in vivo, J. Neurosci., 23, 5645, 10.1523/JNEUROSCI.23-13-05645.2003 Burns, 2006, Cholesterol distribution, not total levels, correlate with altered amyloid precursor protein processing in statin-treated mice, Neuromol. Med., 8, 319, 10.1385/NMM:8:3:319 Busciglio, 1993, Generation of, β-amyloid in the secretory pathway in neuronal and nonneuronal cells, Proc. Natl. Acad. Sci. U. S. A., 90, 2092, 10.1073/pnas.90.5.2092 Buxbaum, 1998, Evidence that tumor necrosis factor a converting enzyme is involved in regulated α-secretase cleavage of the Alzheimer amyloid protein precursor, J. Biol. Chem., 273, 27765, 10.1074/jbc.273.43.27765 Buxbaum, 2001, Cholesterol depletion with physiological concentrations of a statin decreases the formation of the Alzheimer amyloid Abeta peptide, J. Alzheimer's Dis., 3, 221, 10.3233/JAD-2001-3207 Buxbaum, 2002, Pharmacological concentrations of the HMG-CoA reductase inhibitor lovastatin decrease the formation of the Alzheimer β-amyloid peptide in vitro and in patients, Front. Biosci., 7, a50 Calleros, 2006, RhoA and p38 MAPK mediate apoptosis induced by cellular cholesterol depletion, Apoptosis, 11, 1161, 10.1007/s10495-006-6980-3 Casserly, 2004, Convergence of atherosclerosis and Alzheimer's disease: inflammation, cholesterol, and misfolded proteins, Lancet, 363, 1139, 10.1016/S0140-6736(04)15900-X Cerezo-Guisado, 2005, Lovastatin inhibits the growth and survival pathway of phosphoinositide 3-kinase/protein kinase B in immortalized rat brain neuroblasts, J. Neurochem., 94, 1277, 10.1111/j.1471-4159.2005.03345.x Chen, 2003, Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke, Ann. Neurol., 53, 743, 10.1002/ana.10555 Chong, 2001, Clinically relevant differences between the statins: implications for therapeutic selection, Am. J. Med., 111, 390, 10.1016/S0002-9343(01)00870-1 Cibičková, 2007, Differential effects of statins and alendronate on cholinesterases in serum and brain of rats, Physiol. Res., 56, 765, 10.33549/physiolres.931121 Clarke, 2007, The HMG-CoA reductase inhibitor, atorvastatin, attenuates the effects of acute administration of amyloid-β1-42 in the rat hippocampus in vivo, Neuropharmacology, 52, 136, 10.1016/j.neuropharm.2006.07.031 Clarke, 2008, A pivotal role for interleukin-4 in atorvastatin-associated neuroprotection in rat brain, J. Biol. Chem., 283, 1808, 10.1074/jbc.M707442200 Cole, 2005, Statins cause intracellular accumulation of amyloid precursor protein, β-secretase-cleaved fragments, and amyloid β-peptide via an isoprenoid-dependent mechanism, J. Biol. Chem., 280, 18755, 10.1074/jbc.M413895200 Corder, 1993, Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families, Science, 261, 921, 10.1126/science.8346443 Cordle, 2005, 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors attenuate β-amyloid-induced microglial inflammatory responses, J. Neurosci., 25, 299, 10.1523/JNEUROSCI.2544-04.2005 Cordle, 2005, Mechanisms of statin-mediated inhibition of small G-protein function, J. Biol. Chem., 280, 34202, 10.1074/jbc.M505268200 Crestini, 2006, Changes in cholesterol metabolism are associated with PS1 and PS2 gene regulation in SK-N-BE, J. Mol. Neurosci., 30, 311, 10.1385/JMN:30:3:311 Crisby, 2002, Statins in the prevention and treatment of Alzheimer disease, Alzheimer Dis. Assoc. Disord., 16, 131, 10.1097/00002093-200207000-00001 Cutler, 2004, Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease, Proc. Natl. Acad. Sci., 101, 2070, 10.1073/pnas.0305799101 De Strooper, 2003, Aph-1, Pen-2, and nicastrin with presenilin generate an active γ-secretase complex, Neuron, 38, 9, 10.1016/S0896-6273(03)00205-8 DeMattos, 2001, Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease, Proc. Natl. Acad. Sci., 98, 8850, 10.1073/pnas.151261398 Désiré, 2005, RAC1 inhibition targets amyloid precursor protein processing by γ-secretase and decreases Aβ production in vitro and in vivo, J. Biol. Chem., 280, 37516, 10.1074/jbc.M507913200 Distl, 2001, Tangle-bearing neurons contain more free cholesterol than adjacent tangle-free neurons, Acta Neuropathol., 101, 547, 10.1007/s004010000314 Dominguez, 2004, Nitric oxide mediates glutamate-evoked dopamine release in the medial preoptic area, Neuroscience, 125, 203, 10.1016/j.neuroscience.2004.01.022 Dugan, 1995, The Ras-related GTP-binding, Rab1B, regulates early steps in esocytic transport and processing of β-amyloid precursor protein, J. Biol. Chem., 270, 10982, 10.1074/jbc.270.18.10982 Ehehalt, 2003, Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts, J. Cell Biol., 160, 113, 10.1083/jcb.200207113 Ehrenstein, 2005, Statins for atherosclerosis—as good as it gets?, N. Engl. J. Med., 252, 73, 10.1056/NEJMe048326 Endo, 1976, Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity, FEBS Lett., 72, 323, 10.1016/0014-5793(76)80996-9 Endres, 2005, Statins and stroke, J. Cereb. Blood Flow Metab., 25, 1093, 10.1038/sj.jcbfm.9600116 Famer, 2004, Rosuvastatin reduces caspase-3 activity and up-regulates α-secretase in human neuroblastoma SH-SY5Y cells exposed to Aβ, Neurosci. Lett., 271, 209, 10.1016/j.neulet.2004.08.069 Fan, 2001, Cholesterol-dependent modulation of tau phosphorylation in cultured neurons, J. Neurochem., 76, 391, 10.1046/j.1471-4159.2001.00063.x Fan, 2002, Cholesterol-dependent modulation of dendrite outgrowth and microtubule stability in cultured neurons, J. Neurochem., 80, 178, 10.1046/j.0022-3042.2001.00686.x Farhangrazi, 1997, High density lipoprotein decreases beta-amyloid toxicity in cortical cell culture, NeuroReport, 8, 1127, 10.1097/00001756-199703240-00013 Farzan, 2000, BACE2, a β-secretase homolog, cleaves at the β site and within the amyloid-β region of the amyloid-β precursor protein, Proc. Natl. Acad. Sci., 97, 9712, 10.1073/pnas.160115697 Fassbender, 2001, Simvastatin strongly reduces levels of Alzheimer's disease b-amyloid peptides Ab42 and Ab40 in vitro and in vivo, Proc. Natl. Acad. Sci., 98, 5856, 10.1073/pnas.081620098 Ferreiro, 2008, The release of calcium from the endoplasmic reticulum induced by amyloid-beta and prion peptides activates the mitochondrial apoptotic pathway, Neurobiol. Dis., 30, 331, 10.1016/j.nbd.2008.02.003 Fischer, 2001, Brain dendritic cells and macrophages/microglia in central nervous system inflammation, J. Immunol., 166, 2717, 10.4049/jimmunol.166.4.2717 Fonseca, A.C., Proena, T., Resende, R., Oliveira, C.R., Pereira, C.M.F., 2009. Neuroprotective effects of statins in an in vitro model of Alzheimer's disease. J. Alzheimer's Dis. 17, 503–517. Franke, 2007, Bcl-2 upregulation and neuroprotection in guinea pig brain following chronic simvastatin treatment, Neurobiol. Dis., 25, 438, 10.1016/j.nbd.2006.10.004 Frears, 1999, The role of cholesterol in the biosynthesis of β-amyloid, NeuroReport, 10, 1699, 10.1097/00001756-199906030-00014 García-Román, 2001, Lovastatin induces apoptosis of spontaneously immortalized rat brain neuroblasts: involvement of nonsterol isoprenoid biosynthesis inhibition, Mol. Cell. Neurosci., 17, 329, 10.1006/mcne.2000.0904 Gellermann, 2006, Alzheimer-like plaque formation by human macrophages Is reduced by fibrillation inhibitors and lovastatin, J. Mol. Biol., 360, 251, 10.1016/j.jmb.2006.05.026 Gong, 2002, Amyloid β-protein affects cholesterol metabolism in cultured neurons: implications for pivotal role of cholesterol in the amyloid cascade, J. Neurosci. Res., 70, 438, 10.1002/jnr.10347 Grace, 2002, Characterization of neuronal dystrophy induced by fibrillar amyloid β: implications for Alzheimer's disease, Neuroscience, 114, 265, 10.1016/S0306-4522(02)00241-5 Graves, 1999, Cognitive decline and Japanese culture in a cohort of older Japanese Americans in King County, WA: the Kame Project, J. Gerontol., B Psychol. Sci. Soc. Sci., 54, S154, 10.1093/geronb/54B.3.S154 Grimm, 2005, Regulation of cholesterol and sphingomyelin metabolism by amyloid-beta and presenilin, Nat. Cell Biol., 7, 1118, 10.1038/ncb1313 Grimm, 2006, Altered membrane fluidity and lipid raft composition in presenilin-deficient cells, Acta Neurol. Scand. Suppl., 185, 27, 10.1111/j.1600-0404.2006.00682.x Gustafson, 2003, An 18-year follow-up of overweight and risk of Alzheimer disease, Arch. Intern. Med., 163, 1524, 10.1001/archinte.163.13.1524 Hartmann, 1997, Distinct sites of intracellular production for Alzheimer's disease Abeta40/42 amyloid peptides, Nat. Med., 3, 1016, 10.1038/nm0997-1016 Hayashi, 2004, A seed for Alzheimer amyloid in the brain, J. Neurosci., 24, 4894, 10.1523/JNEUROSCI.0861-04.2004 Helzner, 2009, Contribution of vascular risk factors to the progression in Alzheimer disease, Arch. Neurol., 66, 343, 10.1001/archneur.66.3.343 Hendrie, 2001, Incidence of dementia and Alzheimer disease in 2 communities: Yoruba residing in Ibadan, Nigeria, and African Americans residing in Indianapolis, Indiana, JAMA, 285, 739, 10.1001/jama.285.6.739 Herz, 2000, Apolipoprotein E receptors: linking brain development and Alzheimer's disease, Nat. Rev., Neurosci., 1, 51, 10.1038/35036221 Heverin, 2004, Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease, J. Lipid Res., 45, 186, 10.1194/jlr.M300320-JLR200 Hofman, 1997, Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study, Lancet, 349, 151, 10.1016/S0140-6736(96)09328-2 Höglund, 2004, Plasma levels of β-amyloid(1-40), β-amyloid(1-42), and total β-amyloid remain unaffected in adult patients with hypercholesterolemia after treatment with statins, Arch. Neurol., 61, 333, 10.1001/archneur.61.3.333 Höglund, 2005, Statin treatment and a disease-specific pattern of β-amyloid peptides in Alzheimer's disease, Exp. Brain Res., 164, 205, 10.1007/s00221-005-2243-8 Honig, 2003, Stroke and the risk of Alzheimer disease, Arch. Neurol., 60, 1707, 10.1001/archneur.60.12.1707 Howland, 1998, Modulation of secreted β-amyloid precursor protein and amyloid β-peptide in brain by cholesterol, J. Biol. Chem., 273, 16576, 10.1074/jbc.273.26.16576 Hutter-Paier, 2004, The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer's disease, Neuron, 44, 227, 10.1016/j.neuron.2004.08.043 Igbavboa, 1996, Increasing age alters transbilayer fluidity and cholesterol asymmetry in synaptic plasma membranes of mice, J. Neurochem., 66, 1717, 10.1046/j.1471-4159.1996.66041717.x Igbavboa, 2003, Cholesterol distribution in the Golgi complex of DITNC1 astrocytes is differentially altered by fresh and aged amyloid β-peptide-(1–42), J. Biol. Chem., 278, 17150, 10.1074/jbc.M301150200 Istvan, 2002, Structural mechanism for statin inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase, Am. Heart J., 144, S27, 10.1067/mhj.2002.130300 Istvan, 2003, Statin inhibition of HMG-CoA reductase: a 3-dimensional view, Atheroscler. Suppl., 4, 3, 10.1016/S1567-5688(03)00003-5 Jantzen, 2007, Isoprenoid depletion by statins antagonizes cytokine-induced down-regulation of endothelial nitric oxide expression and increases NO synthase activity in human umbilical vein endothelial cells, J. Physiol. Pharmacol., 58, 503 Jiang, 2007, The inhibitory effect of simvastatin on the ADMA-induced inflammatory reaction is mediated by MAPK pathways in endothelial cells, Biochem. Cell. Biol., 85, 66, 10.1139/o06-146 Jick, 2000, Statins and the risk of dementia, Lancet, 356, 1627, 10.1016/S0140-6736(00)03155-X Jin, 2004, Intracellular accumulation of amyloidogenic fragments of amyloid-β precursor protein in neurons with Niemann-Pick type C defects is associated with endosomal abnormalities, Am. J. Pathol., 164, 975, 10.1016/S0002-9440(10)63185-9 Johnson-Anuna, 2005, Chronic administration of statins alters multiple gene expression patterns in mouse cerebral cortex, J. Pharmacol. Exp. Ther., 312, 786, 10.1124/jpet.104.075028 Johnson-Anuna, 2007, Simvastatin protects neurons from cytotoxicity by up-regulating Bcl-2 mRNA and protein, J. Neurochem., 101, 77, 10.1111/j.1471-4159.2006.04375.x Jones, 2003, Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR⁎ Trial), Am. J. Cardiol., 92, 152, 10.1016/S0002-9149(03)00530-7 Kaether, 2004, A lipid boundary separates APP and secretases and limits amyloid β-peptide generation, J. Cell Biol., 167, 809, 10.1083/jcb.200410090 Kakio, 2002, Interactions of amyloid β-protein with various gangliosides in raft-like membranes: importance of GM1 ganglioside-bound form as an endogenous seed for Alzheimer Amyloid, Biochemistry, 41, 7385, 10.1021/bi0255874 Kaneko, 2001, Drastic neuronal loss in vivo by β-amyloid racemized at Ser26 residue: conversion of non-toxic [D-Ser26]β-amyloid 1–14 to toxic and proteinase-resistant fragments, Neuroscience, 104, 1003, 10.1016/S0306-4522(01)00155-5 Karten, 2002, Cholesterol accumulates in cell bodies, but is decreased in distal axons, of Niemann-Pick C1-deficient neurons, J. Neurochem., 83, 1154, 10.1046/j.1471-4159.2002.01220.x Kawas, 2000, Age-specific incidence rates of Alzheimer's disease: the Baltimore Longitudinal Study of Aging, Neurology, 54, 2072, 10.1212/WNL.54.11.2072 Kiener, 2001, Stimulation of inflammatory responses in vitro and in vivo by lipophilic HMG-CoA reductase inhibitors, Int. Immunopharmacol., 1, 105, 10.1016/S0162-3109(00)00272-1 Kirsh, 2003, Statins effects on cholesterol micro-domains in plasma membranes, Biochem. Pharmacol., 65, 843, 10.1016/S0006-2952(02)01654-4 Kivipelto, 2001, Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study, BMJ, 322, 1447, 10.1136/bmj.322.7300.1447 Kivipelto, 2002, Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease, Ann. Int. Med., 137, 149, 10.7326/0003-4819-137-3-200208060-00006 Koike, 1999, Membrane-anchored metalloprotease MDC9 has an a-secretase activity responsible for processing the amyloid precursor protein, Biochem. J., 343, 371, 10.1042/bj3430371 Kojro, 2001, Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10, Proc. Natl. Acad. Sci., 98, 5815, 10.1073/pnas.081612998 Koldamova, 2003, 22R-Hydroxycholesterol and 9-cis-retinoic acid Induce ATP-binding cassette transporter A1 expression and cholesterol efflux in brain cells and decrease amyloid β secretion, J. Biol. Chem., 278, 13244, 10.1074/jbc.M300044200 Koudinov, 2001, Essential role for cholesterol in synaptic plasticity and neuronal degeneration, FASEB J., 15, 1858, 10.1096/fj.00-0815fje Koudinov, 2005, Cholesterol homeostasis failure as a unifying cause of synaptic degeneration, J. Neurol. Sci., 229–230, 233, 10.1016/j.jns.2004.11.036 Kuo, 1998, Elevated low-density lipoprotein in Alzheimer's disease correlates with brain Aβ 1–42 levels, Biochem. Biophys. Res. Commun., 252, 711, 10.1006/bbrc.1998.9652 Kureishi, 2000, The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals, Nat. Med., 6, 1004, 10.1038/79510 Lacko, 1983, Lecithin: cholesterol acyltransferase in Down's syndrome, Clin. Chim. Acta, 132, 133, 10.1016/0009-8981(83)90241-3 Leissring, 2002, A physiologic signaling role for the γ-secretase-derived intracellular fragment of APP, Proc. Natl. Acad. Sci., 99, 4697, 10.1073/pnas.072033799 Li, 2005, Effects of Abeta25-35 on neurogenesis in the adult mouse subventricular zone and dentate gyrus, Neurol. Res., 27, 218, 10.1179/016164105X35585 Li, 2002, Inhibition of protein geranylgeranylation and RhoA/RhoA kinase pathway induces apoptosis in human endothelial cells, J. Biol. Chem., 277, 15309, 10.1074/jbc.M201253200 Li, 2004, Statin therapy and risk of dementia in the elderly: a community-based prospective cohort study, Neuron, 63, 1624 Li, 2006, Simvastatin enhances learning and memory independent of amyloid load in mice, Ann. Neurol., 60, 729, 10.1002/ana.21053 Liao, 2002, Isoprenoids as mediators of the biological effects of statins, J. Clin. Invest., 110, 285, 10.1172/JCI0216421 Liu, 1998, Amyloid β peptide alters intracellular vesicle trafficking and cholesterol homeostasis, Proc. Natl. Acad. Sci. U. S. A., 95, 13266, 10.1073/pnas.95.22.13266 Liu, 2004, Residues 17–20 and 30–35 of beta-amyloid play critical roles in aggregation, J. Neurosci. Res., 75, 162, 10.1002/jnr.10859 Locatelli, 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, 10.1001/archneur.59.2.213 Lütjohann, 2003, 24S-hydroxycholesterol: a marker of brain cholesterol metabolism, Pharmacopsychiatry, 36, S102, 10.1055/s-2003-43053 Lütjohann, 2000, Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients, J. Lipid Res., 41, 195, 10.1016/S0022-2275(20)32052-6 Mackay, 1998, Rho GTPases, J. Biol. Chem., 273, 20685, 10.1074/jbc.273.33.20685 Malaplate-Armand, 2006, Soluble oligomers of amyloid-B peptide induce neuronal apoptosis by activating a cPLA2-dependent sphingomyelinase-ceramide pathway, Neurobiol. Dis., 23, 178, 10.1016/j.nbd.2006.02.010 Marx, 2001, Alzheimer's disease. Bad for the heart, bad for the mind?, Science, 294, 508, 10.1126/science.294.5542.508 März, 2007, Statins induce differentiation and cell death in neurons and astroglia, GLIA, 55, 1, 10.1002/glia.20422 Mauch, 2001, CNS synaptogenesis promoted by glia-derived cholesterol, Science, 294, 1354, 10.1126/science.294.5545.1354 McConlogue, 1996, Differential effects of a Rab6 mutant on secretory versus amyloidogenic processing of Alzheimer's beta-amyloid precursor protein, J. Biol. Chem., 271, 1343, 10.1074/jbc.271.3.1343 Merla, 2007, The central role of adenosine in statin-induced ERK1/2, Akt, and eNOS phosphorylation, Am. J. Physiol., Heart Circ. Physiol., 293, H1918, 10.1152/ajpheart.00416.2007 Meske, 2003, Blockade of HMG-CoA reductase activity causes changes in microtubule-stabilizing protein tau via suppression of geranylgeranyl pyrophosphate formation: implications for Alzheimer's disease, Eur. J. Neurosci., 17, 93, 10.1046/j.1460-9568.2003.02433.x Michikawa, 2001, A novel action of Alzheimer's amyloid β-protein (Aβ): oligomeric Aβ promotes lipid release, J. Neurosci., 21, 7226, 10.1523/JNEUROSCI.21-18-07226.2001 Mielke, 2005, High total cholesterol levels in late life associated with a reduced risk of dementia, Neurology, 64, 1689, 10.1212/01.WNL.0000161870.78572.A5 Mizuno, 1999, Cholesterol-dependent generation of a seeding amyloid beta-protein in cell culture, J. Biol. Chem., 274, 15110, 10.1074/jbc.274.21.15110 Montaner, 1998, Multiple signalling pathways lead to the activation of the nuclear factor kappaB by the Rho family of GTPases, J. Biol. Chem., 273, 12779, 10.1074/jbc.273.21.12779 Mozayan, 2007, Statins prevent cholinesterase inhibitor blockade of sympathetic α7-nAChR-mediated currents in rat superior cervical ganglion neurons, Am. J. Physiol., Heart Circ. Physiol., 293, H1737, 10.1152/ajpheart.00269.2007 Mulhaupt, 2003, Statins (HMG-CoA reductase inhibitors) reduce CD40 expression in human vascular cells, Cardiovasc. Res., 59, 755, 10.1016/S0008-6363(03)00515-7 Nagy, 2005, The last neuronal division: a unifying hypothesis for the pathogenesis of Alzheimer's disease, J. Cell Mol. Med., 9, 531, 10.1111/j.1582-4934.2005.tb00485.x Nelson, 2005, Oxidation of cholesterol by amyloid precursor protein and β-amyloid peptide, J. Biol. Chem., 280, 7377, 10.1074/jbc.M409071200 Nixon, 2004, Niemann-Pick type C disease and Alzheimer's disease: the APP-endosome connection fattens up, Am. J. Pathol., 64, 757, 10.1016/S0002-9440(10)63163-X Olesen, 2000, High density lipoprotein inhibits assembly of amyloid beta-peptides into fibrils, Biochem. Biophys. Res. Commun., 270, 62, 10.1006/bbrc.2000.2372 Ong, 2001, Neurodegeneration in Niemann-Pick type C disease mice, Exp. Brain Res., 141, 218, 10.1007/s002210100870 Ostrowski, 2007, Statins reduce amyloid-β production through inhibition of protein isoprenylation, J. Biol. Chem., 282, 26832, 10.1074/jbc.M702640200 Pahan, 1997, Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages, J. Clin. Invest., 100, 2671, 10.1172/JCI119812 Panza, 2006, Lipid metabolism in cognitive decline and dementia, Brain Res. Rev., 51, 275, 10.1016/j.brainresrev.2005.11.007 Panza, 2007, Total cholesterol levels and the risk of mild cognitive impairment and Alzheimer'disease, JAGS Lett. Ed., 55, 133, 10.1111/j.1532-5415.2006.01003.x Papassotiropoulos, 2002, 24S-hydroxycholesterol in cerebrospinal fluid is elevated in early stages of dementia, J. Psychiatr. Res., 36, 27, 10.1016/S0022-3956(01)00050-4 Papassotiropoulos, 2003, Increased brain beta-amyloid load, phosphorylated tau, and risk of Alzheimer disease associated with an intronic CYP46 polymorphism, Arch. Neurol., 60, 29, 10.1001/archneur.60.1.29 Pappolla, 2003, Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology, Neurology, 61, 199, 10.1212/01.WNL.0000070182.02537.84 Paris, 2002, Statins inhibit A beta-neurotoxicity in vitro and A beta-induced vasoconstriction and inflammation in rat aortae, Atherosclerosis, 161, 293, 10.1016/S0021-9150(01)00660-8 Park, 2003, Lovastatin enhances Aβ production and senile plaque deposition in female Tg2576 mice, Neurobiol. Aging, 24, 637, 10.1016/S0197-4580(02)00155-0 Parsons, 2006, Statins inhibit the dimerization of beta-secretase via both isoprenoid- and cholesterol-mediated mechanisms, Biochem. J., 399, 205, 10.1042/BJ20060655 Pedrini, 2005, Modulation of statin-activated shedding of Alzheimer APP ectodomain by ROCK, PLOS Med., 2, 69, 10.1371/journal.pmed.0020018 Peila, 2002, Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: the Honolulu–Asia aging study, Diabetes, 51, 1256, 10.2337/diabetes.51.4.1256 Petanceska, 2002, Statin therapy for Alzheimer's disease: will it work?, J. Mol. Neurosci., 19, 155, 10.1007/s12031-002-0026-2 Pfrieger, 2003, Outsourcing in the brain: do neurons depend on cholesterol delivery by astrocytes?, BioEssays, 25, 72, 10.1002/bies.10195 Poirier, 2000, Apolipoprotein E and Alzheimer's disease. A role in amyloid catabolism, Ann. N.Y. Acad. Sci., 924, 81, 10.1111/j.1749-6632.2000.tb05564.x Pooler, 2006, The 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitor pravastatin enhances neurite outgrowth in hippocampal neurons, J. Neurochem., 97, 716, 10.1111/j.1471-4159.2006.03763.x Postina, 2004, A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model, J. Clin. Invest., 113, 1456, 10.1172/JCI20864 Puglielli, 2001, Acyl-coenyme A: cholesterol acyltransferase modulates the generation of the amyloid beta-peptide, Nat. Cell Biol., 3, 905, 10.1038/ncb1001-905 Puglielli, 2003, Alzheimer's disease: the cholesterol connection, Nat. Neurosci., 6, 345, 10.1038/nn0403-345 Puglielli, 2004, Role of acyl-coenzyme A cholesterol acyltransferase activity in the processing of the amyloid precursor protein, J. Mol. Neurosci., 24, 93, 10.1385/JMN:24:1:093 Qiu, 2003, Pulse pressure and risk of Alzheimer disease in persons aged 75 years and older: a community based, longitudinal study, Stroke, 34, 594, 10.1161/01.STR.0000060127.96986.F4 Refolo, 2000, Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model, Neurobiol. Dis., 7, 321, 10.1006/nbdi.2000.0304 Refolo, 2001, A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease, Neurobiol. Dis., 8, 890, 10.1006/nbdi.2001.0422 Repetto, 2004, BACE1 overexpression regulates amyloid precursor protein cleavage and interaction with the ShcA adapter, Ann. N.Y. Acad. Sci., 1030, 330, 10.1196/annals.1329.041 Resende, 2007, Susceptibility of hippocampal neurons to Aβ peptide toxicity is associated with perturbation of Ca2+ homeostasis, Brain Res., 1143, 11, 10.1016/j.brainres.2007.01.071 Resende, 2008, Neurotoxic effect of oligomeric and fibrillar species of Aβ1-42 peptide: involvement of endoplasmic reticulum calcium release in oligomers-induced cell death, Neuroscience, 155, 725, 10.1016/j.neuroscience.2008.06.036 Romas, 1999, APOE genotype, plasma lipids, lipoproteins, and AD in community elderly, Neurology, 53, 517, 10.1212/WNL.53.3.517 Runz, 2002, Inhibition of intracellular cholesterol transport alters presenilin localization and amyloid precursor protein processing in neuronal cells, J. Neurosci., 22, 1679, 10.1523/JNEUROSCI.22-05-01679.2002 Rutishauser, 2006, The role of statins in clinical medicine—LDL-cholesterol lowering and beyond, Swiss Med. Wkly., 136, 41 Sabbagh, 2004, Is there a characteristic lipid profile in Alzheimer's disease, J. Alzheimer's Dis., 6, 585, 10.3233/JAD-2004-6602 Sala, 2008, HMG-CoA reductase inhibitor simvastatin inhibits cell cycle progression at the G1/S checkpoint in immortalized lymphocytes from Alzheimer's disease patients independently of cholesterol lowering effects, J. Pharmacol. Exp. Ther., 324, 352, 10.1124/jpet.107.128959 Salins, 2007, Lovastatin protects human neurons against Abeta-induced toxicity and causes activation of beta-catenin-TCF/LEF signaling, Neurosci. Lett., 412, 211, 10.1016/j.neulet.2006.07.045 Schneider, 2006, Cholesterol depletion reduces aggregation of amyloid-beta peptide in hippocampal neurons, Neurobiol. Dis., 23, 573, 10.1016/j.nbd.2006.04.015 Schönknecht, 2002, Cerebrospinal fluid 24S-hydroxycholesterol is increased in patients with Alzheimer's disease compared to healthy controls, Neurosci. Lett., 324, 83, 10.1016/S0304-3940(02)00164-7 Schroeder, 2001, Recent advances in membrane microdomains: rafts, caveolae, and intracellular cholesterol trafficking, Exp. Biol. Med., 226, 873, 10.1177/153537020122601002 Schulz, 2004, HMG-CoA reductase inhibition causes neurite loss by interfering with geranylgeranylpyrophosphate synthesis, J. Neurochem., 89, 24, 10.1046/j.1471-4159.2003.02305.x Shepherd, 2002, Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial, Lancet, 360, 1623, 10.1016/S0140-6736(02)11600-X Shie, 2002, Diet-induced hypercholesterolemia enhances brain Aβ accumulation in transgenic mice, NeuroReport, 13, 455, 10.1097/00001756-200203250-00019 Shishehbor, 2003, Statins promote potent systemic antioxidant effects through specific inflammatory pathways, Circulation, 108, 426, 10.1161/01.CIR.0000080895.05158.8B Si, 2005, Statins prevent beta-amyloid inhibition of sympathetic alpha7-nAChR-mediated nitrergic neurogenic dilation in porcine basilar arteries, J. Cereb. Blood Flow Metab., 25, 1573, 10.1038/sj.jcbfm.9600232 Simons, 1998, Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neurons, Proc. Natl. Acad. Sci. U. S. A., 95, 6460, 10.1073/pnas.95.11.6460 Simons, 2001, Cholesterol and Alzheimer's disease: is there a link?, Neurology, 57 Sjögren, 2003, Treatment with simvastatin in patients with Alzheimer's disease lowers both α- and β-cleaved APP, Dement. Geriatr. Cogn. Disord., 16, 25, 10.1159/000069989 Skovronsky, 2000, Protein kinase C-dependent α-secretase competes with β-secretase for cleavage of amyloid-β precursor protein in the trans-golgi network, J. Biol. Chem., 275, 2568, 10.1074/jbc.275.4.2568 Solfrizzi, 2004, Vascular risk factors, incidence of MCI, and rates of progression to dementia, Neurology, 63, 1882, 10.1212/01.WNL.0000144281.38555.E3 Sparks, 1990, Cortical senile plaques in coronary artery disease, aging and Alzheimer's disease, Neurobiol. Aging, 11, 601, 10.1016/0197-4580(90)90024-T Sparks, 2003, Is cholesterol a culprit in Alzheimer's disease?, Int. Psychogeriatr., 15, 153, 10.1017/S1041610203009128 Sparks, 2005, Atorvastatin for the treatment of mild to moderate Alzheimer disease, Arch. Neurol., 62, 753, 10.1001/archneur.62.5.753 Sponne, 2004, Membrane cholesterol interferes with neuronal apoptosis induced by soluble oligomers but not fibrils of amyloid-β peptide, FASEB J., 18, 836, 10.1096/fj.03-0372fje Stephens, 1996, Metabolites of the β-amyloid precursor protein generated by β-secretase localise to the trans-Golgi network and late endosome in 293 cells, J. Neurosci. Res., 46, 211, 10.1002/(SICI)1097-4547(19961015)46:2<211::AID-JNR9>3.0.CO;2-K Strittmatter, 1993, Binding of human apolipoprotein E to synthetic amyloid β peptide: isoform-specific effects and implications for late-onset Alzheimer disease, Proc. Natl. Acad. Sci. U.S.A., 90, 8098, 10.1073/pnas.90.17.8098 Subasinghe, 2003, Cholesterol is necessary both for the toxic effect of Aβ peptides on vascular smooth muscle cells and for Aβ binding to vascular smooth muscle cell membranes, J. Neurochem., 84, 471, 10.1046/j.1471-4159.2003.01552.x Sun, 2003, Pravastatin inhibits pro-inflammatory effects of Alzheimer's peptide Aβ1–42 in glioma cell culture in vitro, Pharmacol. Res., 47, 119, 10.1016/S1043-6618(02)00288-8 Svennerholm, 1994, Membrane lipids of adult human brain: lipid composition of frontal and temporal lobe in subjects of age 20 to 100 years, J. Neurochem., 63, 1802, 10.1046/j.1471-4159.1994.63051802.x Tadiboyina, 2005, Treatment of dyslipidemia with lovastatin and ezetimibe in an adolescent with cholesterol ester storage disease, Lipids Health Dis., 4, 26, 10.1186/1476-511X-4-26 Tanaka, 2000, Geranylgeranyl-pirophosphate, 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, 2852, 10.1523/JNEUROSCI.20-08-02852.2000 Tomita, 1997, The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid beta protein ending at the 42nd (or 43rd) residue, Proc. Natl. Acad. Sci. U. S. A., 94, 2025, 10.1073/pnas.94.5.2025 Townsend, 2004, Lovastatin modulation of microglial activation via suppression of functional CD40 expression, J. Neurosci. Res., 78, 167, 10.1002/jnr.20234 Urano, 2005, Association of active γ-secretase complex with lipid rafts, J. Lipid Res., 46, 904, 10.1194/jlr.M400333-JLR200 Urbich, 2002, Double-edged role of statins in angiogenesis signaling, Circ. Res., 90, 737, 10.1161/01.RES.0000014081.30867.F8 Veillard, 2002, Statins: the new aspirin?, Cell. Mol. Life Sci., 59, 1771, 10.1007/PL00012505 Vetrivel, 2004, Association of γ-secretase with lipid raft in post-Golgi and endossome membrane, J. Biol. Chem., 279, 44945, 10.1074/jbc.M407986200 Wagner, 2002, 3-Hydroxy-3-methylglutaryl coenzyme A reductase-independent inhibition of CD40 expression by atorvastatin in human endothelial cells, Arterioscler. Thromb. Vasc. Biol., 22, 1784, 10.1161/01.ATV.0000037098.20829.31 Wahrle, 2002, Cholesterol-dependent γ-secretase activity in buoyant cholesterol-rich membrane microdomains, Neurobiol. Dis., 9, 11, 10.1006/nbdi.2001.0470 Wang, 2005, High doses of simvastatin upregulate dopamine D1 and D2 receptor expression in the rat prefrontal cortex: possible involvement of endothelial nitric oxide synthase, Br. J. Pharmacol., 144, 933, 10.1038/sj.bjp.0706106 Weis, 2002, Statins have biphasic effects on angiogenesis, Circulation, 105, 739, 10.1161/hc0602.103393 Weitz-Schmidt, 2001, Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site, Nat. Med., 7, 687, 10.1038/89058 Wilson, 1997, Free fatty acids stimulate the polymerization of tau and amyloid β peptides: in vitro evidence for a common effector of pathogenesis in Alzheimer's disease, Am. J. Pathol., 150, 2181 Wolf, 2004, Serum lipids and hippocampal volume: the link to Alzheimer's disease?, Ann. Neurol., 56, 745, 10.1002/ana.20289 Wolozin, 2001, A fluid connection: cholesterol and Aβ, Proc. Natl. Acad. Sci. U. S. A., 98, 5371, 10.1073/pnas.101123198 Wolozin, 2002, Cholesterol and Alzheimer's disease, Biochem. Soc. Trans., 30, 525, 10.1042/bst0300525 Wolozin, 2004, Cholesterol, statins and dementia, Curr. Opin. Lipid., 15, 667, 10.1097/00041433-200412000-00007 Wood, 2002, Brain membrane cholesterol domains, aging and amyloid beta-peptides, Neurobiol. Aging, 23, 685, 10.1016/S0197-4580(02)00018-0 Wu, 1996, Changes in membrane properties during energy depletion-induced cell injury studied with fluorescence microscopy, Biophys. J., 71, 91, 10.1016/S0006-3495(96)79243-3 Xiao, 2002, Huperzine A attenuates amyloid β-peptide fragment 25-35-induced apoptosis in rat cortical neurons via inhibiting reactive oxygen species formation and caspase-3 activation, J. Neurosci. Res., 67, 30, 10.1002/jnr.10075 Xiu, 2005, Lovastatin stimulates up-regulation of α7 nicotinic receptors in cultured neurons without cholesterol dependency, a mechanism involving production of the α-form of secreted amyloid precursor protein, J. Neurosci. Res., 82, 531, 10.1002/jnr.20658 Yaffe, 2002, Serum lipoprotein levels, statin use, and cognitive function in older women, Arch. Neurol., 59, 378, 10.1001/archneur.59.3.378 Yamazaki, 2001, Accumulation and aggregation of amyloid β-protein in late endosomes of Niemann-pick type C cells, J. Biol. Chem., 276, 4454, 10.1074/jbc.M009598200 Yao, 2002, 22R-Hydroxycholesterol protects neuronal cells from beta-amyloid-induced cytotoxicity by binding to beta-amyloid peptide, Neurochemistry, 83, 1110, 10.1046/j.1471-4159.2002.01202.x Yasojima, 2001, 3-Hydroxy-3-methylglutaryl-coenzyme A reductase mRNA in Alzheimer and control brain, NeuroReport, 12, 2935, 10.1097/00001756-200109170-00036 Youssef, 2002, The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease, Nature, 420, 78, 10.1038/nature01158 Zacco, 2003, 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors protect cortical neurons from excitotoxicity, J. Neurosci., 23, 11104, 10.1523/JNEUROSCI.23-35-11104.2003 Zandi, 2005, Do statins reduce risk of incident dementia and Alzheimer disease? The Cache County Study, Arch. Genet. Psychiatry, 62, 217, 10.1001/archpsyc.62.2.217 Żekanowski, 2004, Genetic aspects of Alzheimer's disease, Acta Neurobiol. Exp., 64, 19 Zhou, 2003, Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Aβ42 by inhibiting Rho, Science, 302, 1215, 10.1126/science.1090154 Zhou, 2007, Prevention and treatment of dementia or Alzheimer's disease by statins: a meta-analysis, Dement. Geriatr. Cogn. Disord., 23, 194, 10.1159/000099037 Zhou, 2008, Geranylgeranyl pyrophosphate stimulates γ-secretase to increase the generation of Aβ and APP-CTFγ, FASEB J., 22, 47, 10.1096/fj.07-8175com Zigman, 2007, Cholesterol level, statin use and Alzheimer's disease in adults with Down syndrome, Neurosci. Lett., 416, 279, 10.1016/j.neulet.2007.02.023