Login Register Cart 0
Generic placeholder image

Current Alzheimer Research

Editor-in-Chief

ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Review Article

ACAT1 as a Therapeutic Target and its Genetic Relationship with Alzheimer's Disease

Author(s): Jessica Sarahi Alavez-Rubio and Teresa Juarez-Cedillo*

Volume 16, Issue 8, 2019

Page: [699 - 709] Pages: 11

DOI: 10.2174/1567205016666190823125245

Price: $65

Abstract

Background: Alzheimer´s disease (AD) is a chronic and progressive disease which impacts caregivers, families and societies physically, psychologically and economically. Currently available drugs can only improve cognitive symptoms, have no impact on progression and are not curative, so identifying and studying new drug targets is important. There are evidences which indicate disturbances in cholesterol homeostasis can be related with AD pathology, especially the compartmentation of intracellular cholesterol and cytoplasmic cholesterol esters formed by acyl-CoA: cholesterol acyltransferase 1 (ACAT1) can be implicated in the regulation of amyloid-beta (Aβ) peptide, involved in AD. Blocking ACAT1 activity, beneficial effects are obtained, so it has been suggested that ACAT1 can be a potential new therapeutic target. The present review discusses the role of cholesterol homeostasis in AD pathology, especially with ACAT inhibitors, and how they have been raised as a therapeutic approach. In addition, the genetic relationship of ACAT and AD is discussed.

Conclusion: Although there are several lines of evidence from cell-based and animal studies that suggest that ACAT inhibition is an effective way of reducing cerebral Aβ, there is still an information gap in terms of mechanisms and concerns to cover before passing to the next level. Additionally, an area of interest that may be useful in understanding AD to subsequently propose new therapeutic approaches is pharmacogenetics; however, there is still a lot of missing information in this area.

Keywords: Alzheimer´s disease, cholesterol metabolism, cholesteryl esters, inhibiting ACAT1, pharmacogenetics, therapeutic target.

« Previous Next »
[1]
Organización Mundial de la Salud y Alzheimer’s Disease International. Demencia: una prioridad en salud pública [monograph on the internet Washington: Organización Panamericana de la Salud; 2013 [cited 2019 jan 20 Available from: https://www.who.int/mental_health/publications/dementia_report_2012/es/
[2]
Di Paolo G, Kim TW. Linking lipids to Alzheimer’s disease: cholesterol and beyond. Nat Rev Neurosci 12(5): 284-96. 2011
[http://dx.doi.org/10.1038/nrn3012] [PMID: 21448224]
[3]
Cubinkova V, Valachova B, Uhrinova I, Brezovakova V, Smolek T, Jadhav S, et al. Alternative hypotheses related to Alzheimer’s disease. Bratisl Lek Listy 119(4): 210-6. 2018
[PMID: 29663818]
[4]
Arenas F, Garcia-Ruiz C, Fernandez-Checa JC. Intracellular cholesterol trafficking and impact in neurodegeneration. Front Mol Neurosci 10: 382. 2017
[http://dx.doi.org/10.3389/fnmol.2017.00382] [PMID: 29204109]
[5]
Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann D, Keller P, et al. Simvastatin strongly reduces levels of Alzheimer’s disease β -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci USA 98(10): 5856-61. 2001
[http://dx.doi.org/10.1073/pnas.081620098] [PMID: 11296263]
[6]
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
[http://dx.doi.org/10.1006/nbdi.2000.0304] [PMID: 10964604]
[7]
Kivipelto M, Helkala EL, Hänninen T, Laakso MP, Hallikainen M, Alhainen K, et al. Midlife vascular risk factors and late-life mild cognitive impairment: A population-based study. Neurology 56(12): 1683-9. 2001
[http://dx.doi.org/10.1212/WNL.56.12.1683] [PMID: 11425934]
[8]
Pappolla MA, Bryant-Thomas TK, Herbert D, Pacheco J, Fabra Garcia M, Manjon M, et al. Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology. Neurology 61(2): 199-205. 2003
[http://dx.doi.org/10.1212/01.WNL.0000070182.02537.84] [PMID: 12874399]
[9]
Whitmer RA, Sidney S, Selby J, Johnston SC, Yaffe K. Midlife cardiovascular risk factors and risk of dementia in late life. Neurology 64(2): 277-81. 2005
[http://dx.doi.org/10.1212/01.WNL.0000149519.47454.F2] [PMID: 15668425]
[10]
Puglielli L, Konopka G, Pack-Chung E, Ingano LA, Berezovska O, Hyman BT, et al. Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid β-peptide. Nat Cell Biol 3(10): 905-12. 2001
[http://dx.doi.org/10.1038/ncb1001-905] [PMID: 11584272]
[11]
Hutter-Paier B, Huttunen HJ, Puglielli L, Eckman CB, Kim DY, Hofmeister A, et al. The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer’s disease. Neuron 44(2): 227-38. 2004
[http://dx.doi.org/10.1016/j.neuron.2004.08.043] [PMID: 15473963]
[12]
Huttunen HJ, Greco C, Kovacs DM. Knockdown of ACAT-1 reduces amyloidogenic processing of APP. FEBS Lett 581(8): 1688-92. 2007
[http://dx.doi.org/10.1016/j.febslet.2007.03.056] [PMID: 17412327]
[13]
Huttunen HJ, Peach C, Bhattacharyya R, Barren C, Pettingell W, Hutter-Paier B, et al. Inhibition of acyl-coenzyme A: cholesterol acyl transferase modulates amyloid precursor protein trafficking in the early secretory pathway. FASEB J 23(11): 3819-28. 2009
[http://dx.doi.org/10.1096/fj.09-134999] [PMID: 19625658]
[14]
Bryleva EY, Rogers MA, Chang CC, Buen F, Harris BT, Rousselet E, et al. ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD. Proc Natl Acad Sci USA 107(7): 3081-6. 2010
[http://dx.doi.org/10.1073/pnas.0913828107] [PMID: 20133765]
[15]
Huttunen HJ, Havas D, Peach C, Barren C, Duller S, Xia W, et al. The acyl-coenzyme A: cholesterol acyltransferase inhibitor CI-1011 reverses diffuse brain amyloid pathology in aged amyloid precursor protein transgenic mice. J Neuropathol Exp Neurol 69(8): 777-88. 2010
[http://dx.doi.org/10.1097/NEN.0b013e3181e77ed9] [PMID: 20613640]
[16]
Murphy SR, Chang CC, Dogbevia G, Bryleva EY, Bowen Z, Hasan MT, et al. Acat1 knockdown gene therapy decreases amyloid-β in a mouse model of Alzheimer’s disease. Mol Ther 21(8): 1497-506. 2013
[http://dx.doi.org/10.1038/mt.2013.118] [PMID: 23774792]
[17]
Shibuya Y, Chang CC, Huang L-H, Bryleva EY, Chang TY. Inhibiting ACAT1/SOAT1 in microglia stimulates autophagy-mediated lysosomal proteolysis and increases Aβ1-42 clearance. J Neurosci 34(43): 14484-501. 2014
[http://dx.doi.org/10.1523/JNEUROSCI.2567-14.2014] [PMID: 25339759]
[18]
Shibuya Y, Niu Z, Bryleva EY. Harris BT2, Murphy SR1, Kheirollah A, et al.Acyl-coenzyme A: cholesterol acyltransferase 1 blockage enhances autophagy in the neurons of triple transgenic Alzheimer’s disease mouse and reduces human P301L-tau content at the presymptomatic stage. Neurobiol Aging 36(7): 2248-59. 2015
[http://dx.doi.org/10.1016/j.neurobiolaging.2015.04.002] [PMID: 25930235]
[19]
Wollmer MA, Streffer JR, Tsolaki M, Grimaldi LM, Lütjohann D, Thal D, et al. Genetic association of acyl-coenzyme A: cholesterol acyltransferase with cerebrospinal fluid cholesterol levels, brain amyloid load, and risk for Alzheimer’s disease. Mol Psychiatry 8(6): 635-8. 2003
[http://dx.doi.org/10.1038/sj.mp.4001296] [PMID: 12851640]
[20]
Zhao FG, Wang YH, Yang JF, Ma QL, Tang Z, Dong XM, et al. Association between acyl-coenzyme A: cholesterol acyltransferase gene and risk for Alzheimer’s disease in Chinese. Neurosci Lett 388(1): 17-20. 2005
[http://dx.doi.org/10.1016/j.neulet.2005.06.020] [PMID: 16043284]
[21]
Bertram L, Hsiao M, Mullin K, Parkinson M, Menon R, Moscarillo TJ, et al. ACAT1 is not associated with Alzheimer’s disease in two independent family-based samples. Mol Psychiatry 10(6): 522-4. 2005
[http://dx.doi.org/10.1038/sj.mp.4001646] [PMID: 15768051]
[22]
Lämsä R, Helisalmi S, Herukka S-K, Tapiola T, Pirttila T, Vepsalainen S, et al. Study on the association between SOAT1 polymorphisms, Alzheimer’s disease risk and the level of CSF biomarkers. Dement Geriatr Cogn Disord 24(2): 146-50. 2007
[http://dx.doi.org/10.1159/000105164] [PMID: 17622762]
[23]
Dietschy JM, Turley SD. Cholesterol metabolism in the brain. Curr Opin Lipidol 12(2): 105-12. 2001
[http://dx.doi.org/10.1097/00041433-200104000-00003] [PMID: 11264981]
[24]
Petrov AM, Kasimov MR, Zefirov AL. Brain cholesterol metabolism and its defects: Linkage to neurodegenerative diseases and synaptic dysfunction. Acta Naturae 8(1): 58-73. 2016
[http://dx.doi.org/10.32607/20758251-2016-8-1-58-73] [PMID: 27099785]
[25]
Canevari L, Clark JB. Alzheimer’s disease and cholesterol: the fat connection. Neurochem Res 32(4-5): 739-50. 2007
[http://dx.doi.org/10.1007/s11064-006-9200-1] [PMID: 17191138]
[26]
Björkhem I, Meaney S, Fogelman AM. Brain cholesterol: long secret life behind a barrier. Arterioscler Thromb Vasc Biol 24(5): 806-15. 2004
[http://dx.doi.org/10.1161/01.ATV.0000120374.59826.1b] [PMID: 14764421]
[27]
Martín MG, Pfrieger F, Dotti CG. Cholesterol in brain disease: sometimes determinant and frequently implicated. EMBO Rep 15(10): 1036-52. 2014
[http://dx.doi.org/10.15252/embr.201439225] [PMID: 25223281]
[28]
Moutinho M, Nunes MJ, Rodrigues E. Cholesterol 24-hydroxylase: Brain cholesterol metabolism and beyond. Biochim Biophys Acta 1861(12 Pt A): 1911-20. 2016
[http://dx.doi.org/10.1016/j.bbalip.2016.09.011] [PMID: 27663182]
[29]
Bogdanovic N, Bretillon L, Lund EG, Diczfalusy U, Lannfelt L, Winblad B, et al. On the turnover of brain cholesterol in patients with Alzheimer’s disease. Abnormal induction of the cholesterol-catabolic enzyme CYP46 in glial cells. Neurosci Lett 314(1-2): 45-8. 2001
[http://dx.doi.org/10.1016/S0304-3940(01)02277-7] [PMID: 11698143]
[30]
Lund EG, Xie C, Kotti T, Turley SD, Dietschy JM, Russell DW. Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover. J Biol Chem 278(25): 22980-8. 2003
[http://dx.doi.org/10.1074/jbc.M303415200] [PMID: 12686551]
[31]
Chang CC, Chen J, Thomas MA, Cheng D, Del Priore VA, Newton RS, et al. Regulation and immunolocalization of acyl-coenzyme A: cholesterol acyltransferase in mammalian cells as studied with specific antibodies. J Biol Chem 270(49): 29532-40. 1995
[http://dx.doi.org/10.1074/jbc.270.49.29532] [PMID: 7493995]
[32]
Chan RB, Oliveira TG, Cortes EP, Honig LS, Duff KE, Small SA, et al. Comparative lipidomic analysis of mouse and human brain with Alzheimer disease. J Biol Chem 287(4): 2678-88. 2012
[http://dx.doi.org/10.1074/jbc.M111.274142] [PMID: 22134919]
[33]
Xie C, Lund EG, Turley SD, Russell DW, Dietschy JM. Quantitation of two pathways for cholesterol excretion from the brain in normal mice and mice with neurodegeneration. J Lipid Res 44(9): 1780-9. 2003
[http://dx.doi.org/10.1194/jlr.M300164-JLR200] [PMID: 12810827]
[34]
Lütjohann D, Meichsner S, Pettersson H. Lipids in Alzheimer’s disease and their potential for therapy. Clin Lipidol 7: 65-78. 2012
[http://dx.doi.org/10.2217/clp.11.74]
[35]
Dietschy JM. Central nervous system: cholesterol turnover, brain development and neurodegeneration. Biol Chem 390(4): 287-93. 2009
[http://dx.doi.org/10.1515/BC.2009.035] [PMID: 19166320]
[36]
Holtzman DM, Morris JC, Goate AM. Alzheimer’s disease: the challenge of the second century. Sci Transl Med 3(77): 77sr1. 2011
[http://dx.doi.org/10.1126/scitranslmed.3002369] [PMID: 21471435]
[37]
Solomon A, Kivipelto M. Cholesterol-modifying strategies for Alzheimer’s disease. Expert Rev Neurother 9(5): 695-709. 2009
[http://dx.doi.org/10.1586/ern.09.25] [PMID: 19402779]
[38]
Alzheimer A. Über einen eigenartigen schweren Erkrankungsprozeß der Hirnrinde. Neurol Zentralblatt 23: 1129-36. 1906
[39]
St Clair D, Rennie M, Slorach E, Norrman J, Yates C, Carothers A. Apolipoprotein E ε 4 allele is a risk factor for familial and sporadic presenile Alzheimer’s disease in both homozygote and heterozygote carriers. J Med Genet 32(8): 642-4. 1995
[http://dx.doi.org/10.1136/jmg.32.8.642] [PMID: 7473659]
[40]
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261(5123): 921-3. 1993
[http://dx.doi.org/10.1126/science.8346443] [PMID: 8346443]
[41]
Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericak-Vance MA, Joo SH, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43(8): 1467-72. 1993
[http://dx.doi.org/10.1212/WNL.43.8.1467] [PMID: 8350998]
[42]
Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 90(5): 1977-81. 1993
[http://dx.doi.org/10.1073/pnas.90.5.1977] [PMID: 8446617]
[43]
Shibuya Y, Chang CC, Chang T-Y. ACAT1/SOAT1 as a therapeutic target for Alzheimer’s disease. Future Med Chem 7(18): 2451-67. 2015
[http://dx.doi.org/10.4155/fmc.15.161] [PMID: 26669800]
[44]
Eckert GP, Wood WG, Müller WE. Effects of aging and beta-amyloid on the properties of brain synaptic and mitochondrial membranes. J Neural Transm (Vienna) 108(8-9): 1051-64. 2001
[http://dx.doi.org/10.1007/s007020170024] [PMID: 11716141]
[45]
Lütjohann D, von Bergmann K. 24S-hydroxycholesterol: a marker of brain cholesterol metabolism. Pharmacopsychiatry 36(Suppl. 2): S102-6. 2003
[http://dx.doi.org/10.1055/s-2003-43053] [PMID: 14574622]
[46]
Wood WG, Li L, Müller WE, Eckert GP. Cholesterol as a causative factor in Alzheimer’s disease: a debatable hypothesis. J Neurochem 129(4): 559-72. 2014
[http://dx.doi.org/10.1111/jnc.12637] [PMID: 24329875]
[47]
Posse de Chaves E. Reciprocal regulation of cholesterol and beta amyloid at the subcellular level in Alzheimer’s disease. Can J Physiol Pharmacol 90(6): 753-64. 2012
[http://dx.doi.org/10.1139/y2012-076] [PMID: 22626060]
[48]
Maulik M, Westaway D, Jhamandas JH, Kar S. Role of cholesterol in APP metabolism and its significance in Alzheimer’s disease pathogenesis. Mol Neurobiol 47(1): 37-63. 2013
[http://dx.doi.org/10.1007/s12035-012-8337-y] [PMID: 22983915]
[49]
Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science 256(5054): 184-5. 1992
[http://dx.doi.org/10.1126/science.1566067] [PMID: 1566067]
[50]
Walker LC, Lynn DG, Chernoff YO. A standard model of Alzheimer’s disease? Prion 12(5-6): 261-5. 2018
[http://dx.doi.org/10.1080/19336896.2018.1525256] [PMID: 30220236]
[51]
Suh YH, Checler F. Amyloid precursor protein, presenilins, and alpha-synuclein: molecular pathogenesis and pharmacological applications in Alzheimer’s disease. Pharmacol Rev 54(3): 469-525. 2002
[http://dx.doi.org/10.1124/pr.54.3.469] [PMID: 12223532]
[52]
Araki W, Tamaoka A. Amyloid beta-protein and lipid rafts: focused on biogenesis and catabolism. Front Biosci 20: 314-24. 2015
[http://dx.doi.org/10.2741/4311] [PMID: 25553453]
[53]
Cordy JM, Hooper NM, Turner AJ. The involvement of lipid rafts in Alzheimer’s disease. Mol Membr Biol 23(1): 111-22. 2006
[http://dx.doi.org/10.1080/09687860500496417] [PMID: 16611586]
[54]
Saxena U. Lipid metabolism and Alzheimer’s disease: pathways and possibilities. Expert Opin Ther Targets 13(3): 331-8. 2009
[http://dx.doi.org/10.1517/14728220902738720] [PMID: 19236155]
[55]
Khan A, Corbett A, Ballard C. Emerging amyloid and tau targeting treatments for Alzheimer’s disease. Expert Rev Neurother 17(7): 697-711. 2017
[http://dx.doi.org/10.1080/14737175.2017.1326819] [PMID: 28490214]
[56]
Kim Y, Kim C, Jang HY, Mook-Jung I. Inhibition of cholesterol biosynthesis reduces γ -secretase activity and amyloid-β generation. J Alzheimers Dis 51(4): 1057-68. 2016
[http://dx.doi.org/10.3233/JAD-150982] [PMID: 26923021]
[57]
Vetrivel KS, Thinakaran G. Amyloidogenic processing of β-amyloid precursor protein in intracellular compartments. Neurology 66(2)(Suppl. 1): S69-73. 2006
[http://dx.doi.org/10.1212/01.wnl.0000192107.17175.39] [PMID: 16432149]
[58]
Djelti F, Braudeau J, Hudry E, Dhenain M, Varin J, Bièche I, et al. CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer’s disease. Brain 138(Pt 8): 2383-98. 2015
[http://dx.doi.org/10.1093/brain/awv166] [PMID: 26141492]
[59]
Cossec JC, Simon A, Marquer C, Moldrich RX, Leterrier C, Rossier J, et al. Clathrin-dependent APP endocytosis and Abeta secretion are highly sensitive to the level of plasma membrane cholesterol. Biochim Biophys Acta 1801(8): 846-52. 2010
[http://dx.doi.org/10.1016/j.bbalip.2010.05.010] [PMID: 20580937]
[60]
Daneschvar HL, Aronson MD, Smetana GW. Do statins prevent Alzheimer’s disease? A narrative review. Eur J Intern Med 26(9): 666-9. 2015
[http://dx.doi.org/10.1016/j.ejim.2015.08.012] [PMID: 26342722]
[61]
Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet 356(9242): 1627-31. 2000
[PMID: 11089820]
[62]
Rockwood K, Kirkland S, Hogan DB, MacKnight C, Merry H, Verreault R, et al. Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch Neurol 59(2): 223-7. 2002
[http://dx.doi.org/10.1001/archneur.59.2.223] [PMID: 11843693]
[63]
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
[http://dx.doi.org/10.1001/archneur.57.10.1439] [PMID: 11030795]
[64]
Swiger KJ, Manalac RJ, Blumenthal RS, Blaha MJ, Martin SS. Statins and cognition: a systematic review and meta-analysis of short- and long-term cognitive effects. Mayo Clin Proc 88(11): 1213-21. 2013
[http://dx.doi.org/10.1016/j.mayocp.2013.07.013] [PMID: 24095248]
[65]
Cramer C, Haan MN, Galea S, Langa KM, Kalbfleisch JD. Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study. Neurology 71(5): 344-50. 2008
[http://dx.doi.org/10.1212/01.wnl.0000319647.15752.7b] [PMID: 18663180]
[66]
Sparks DL, Kryscio RJ, Sabbagh MN, Connor DJ, Sparks LM, Liebsack C. Reduced risk of incident AD with elective statin use in a clinical trial cohort. Curr Alzheimer Res 5(4): 416-21. 2008
[http://dx.doi.org/10.2174/156720508785132316] [PMID: 18690839]
[67]
Haag MDM, Hofman A, Koudstaal PJ, Stricker BH, Breteler MM. Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study. J Neurol Neurosurg Psychiatry 80(1): 13-7. 2009
[http://dx.doi.org/10.1136/jnnp.2008.150433] [PMID: 18931004]
[68]
Arvanitakis Z, Schneider JA, Wilson RS, Bienias JL, Kelly JF, Evans DA, et al. Statins, incident Alzheimer disease, change in cognitive function, and neuropathology. Neurology 2008; 70(19 Pt 2): 1795-802.
[http://dx.doi.org/10.1212/01.wnl.0000288181.00826.63] [PMID: 18199831]
[69]
McGuinness B, Craig D, Bullock R, Passmore P. Statins for the prevention of dementia. Cochrane Database Syst Rev (1): CD003160 2016
[PMID: 26727124]
[70]
Bhattacharyya R, Kovacs DM. ACAT inhibition and amyloid beta reduction. Biochim Biophys Acta 1801(8): 960-5. 2010
[http://dx.doi.org/10.1016/j.bbalip.2010.04.003] [PMID: 20398792]
[71]
Li J, Gu D, Lee SSY, Song B, Bandyopadhyay S, Chen S, et al. Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer. Oncogene 35(50): 6378-88. 2016
[http://dx.doi.org/10.1038/onc.2016.168] [PMID: 27132508]
[72]
Bemlih S, Poirier MD, El Andaloussi A. Acyl-coenzyme A: cholesterol acyltransferase inhibitor Avasimibe affect survival and proliferation of glioma tumor cell lines. Cancer Biol Ther 9(12): 1025-32. 2010
[http://dx.doi.org/10.4161/cbt.9.12.11875] [PMID: 20404512]
[73]
Lee SS, Li J, Tai JN, Ratliff TL, Park K, Cheng JX. Avasimibe encapsulated in human serum albumin blocks cholesterol esterification for selective cancer treatment. ACS Nano 9(3): 2420-32. 2015
[http://dx.doi.org/10.1021/nn504025a] [PMID: 25662106]
[74]
Antalis CJ, Arnold T, Rasool T, Lee B, Buhman KK, Siddiqui RA. High ACAT1 expression in estrogen receptor negative basal-like breast cancer cells is associated with LDL-induced proliferation. Breast Cancer Res Treat 122(3): 661-70. 2010
[http://dx.doi.org/10.1007/s10549-009-0594-8] [PMID: 19851860]
[75]
Rogers MA, Liu J, Song BL, Li BL, Chang CC, Chang TY. Acyl-CoA:cholesterol acyltransferases (ACATs/SOATs): Enzymes with multiple sterols as substrates and as activators. J Steroid Biochem Mol Biol 151: 102-7. 2015
[http://dx.doi.org/10.1016/j.jsbmb.2014.09.008] [PMID: 25218443]
[76]
Chang CC, Huh HY, Cadigan KM, Chang TY. Molecular cloning and functional expression of human acyl-coenzyme A:cholesterol acyltransferase cDNA in mutant Chinese hamster ovary cells. J Biol Chem 268(28): 20747-55. 1993
[PMID: 8407899]
[77]
Tajima Y, Ishikawa M, Maekawa K, Murayama M, Senoo Y, Nishimaki-Mogami T, et al. Lipidomic analysis of brain tissues and plasma in a mouse model expressing mutated human amyloid precursor protein/tau for Alzheimer’s disease. Lipids Health Dis 12: 68. 2013
[http://dx.doi.org/10.1186/1476-511X-12-68] [PMID: 23659495]
[78]
Roth BD. ACAT inhibitors: evolution from cholesterol-absorption inhibitors to antiatherosclerotic agents. Drug Discov Today 3: 19-25. 1998
[http://dx.doi.org/10.1016/S1359-6446(97)01123-9]
[79]
Hainer JW, Terry JG, Connell JM, Zyruk H, Jenkins RM, Shand DL, et al. Effect of the acyl-CoA:cholesterol acyltransferase inhibitor DuP 128 on cholesterol absorption and serum cholesterol in humans. Clin Pharmacol Ther 56(1): 65-74. 1994
[http://dx.doi.org/10.1038/clpt.1994.102] [PMID: 8033496]
[80]
Llaverias G, Alegret M. Inhibidores de la acil coenzima A:colesterol aciltransferasa (ACAT): mecanismos y perspectivas terapéuticas. Clin Invest Arter 16: 250-61. 2004
[http://dx.doi.org/10.1016/S0214-9168(04)79002-6]
[81]
Bocan TM, Mueller SB, Uhlendorf PD, Newton RS, Krause BR. Comparison of CI-976, an ACAT inhibitor, and selected lipid-lowering agents for antiatherosclerotic activity in iliac-femoral and thoracic aortic lesions. A biochemical, morphological, and morphometric evaluation. Arterioscler Thromb 11(6): 1830-43. 1991
[http://dx.doi.org/10.1161/01.ATV.11.6.1830] [PMID: 1931885]
[82]
Lee HT, Sliskovic DR, Picard JA, Roth BD, Wierenga W, Hicks JL, et al. Inhibitors of acyl-CoA: cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. CI-1011: an acyl sulfamate with unique cholesterol-lowering activity in animals fed noncholesterol-supplemented diets. J Med Chem 39(26): 5031-4. 1996
[http://dx.doi.org/10.1021/jm960674d] [PMID: 8978833]
[83]
Tardif JC, Grégoire J, L’Allier PL, et al. Avasimibe and Progression of Lesions on UltraSound (A-PLUS) Investigators. Effects of the acyl coenzyme A:cholesterol acyltransferase inhibitor avasimibe on human atherosclerotic lesions. Circulation 2004; 110(21): 3372-7.
[http://dx.doi.org/10.1161/01.CIR.0000147777.12010.EF] [PMID: 15533865]
[84]
Nicholls SJ, Sipahi I, Schoenhagen P, Wisniewski L, Churchill T, Crowe T, et al. ACTIVATE Investigators.Intravascular ultrasound assessment of novel antiatherosclerotic therapies: rationale and design of the Acyl-CoA:Cholesterol Acyltransferase Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE) Study. Am Heart J 152(1): 67-74. 2006
[http://dx.doi.org/10.1016/j.ahj.2005.10.025] [PMID: 16824833]
[85]
Meuwese MC, de Groot E, Duivenvoorden R, Trip MD, Ose L, Maritz FJ, et al. CAPTIVATE Investigators. ACAT inhibition and progression of carotid atherosclerosis in patients with familial hypercholesterolemia: the CAPTIVATE randomized trial. JAMA 301(11): 1131-9. 2009
[http://dx.doi.org/10.1001/jama.301.11.1131] [PMID: 19293413]
[86]
Nissen SE, Tuzcu EM, Brewer HB, Sipahi I, Nicholls SJ, Ganz P, et al. ACAT Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE) Investigators.Effect of ACAT inhibition on the progression of coronary atherosclerosis. N Engl J Med 354(12): 1253-63. 2006
[http://dx.doi.org/10.1056/NEJMoa054699] [PMID: 16554527]
[87]
Hickman SE, Allison EK, El Khoury J. Microglial dysfunction and defective β-amyloid clearance pathways in aging Alzheimer’s disease mice. J Neurosci 28(33): 8354-60. 2008
[http://dx.doi.org/10.1523/JNEUROSCI.0616-08.2008] [PMID: 18701698]
[88]
Griciuc A, Serrano-Pozo A, Parrado AR, Lesinski AN, Asselin CN, Mullin K, et al. Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78(4): 631-43. 2013
[http://dx.doi.org/10.1016/j.neuron.2013.04.014] [PMID: 23623698]
[89]
Mizushima N. Autophagy: process and function. Genes Dev 21(22): 2861-73. 2007
[http://dx.doi.org/10.1101/gad.1599207] [PMID: 18006683]
[90]
Caccamo A, Majumder S, Richardson A, Strong R, Oddo S. Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-β, and Tau: effects on cognitive impairments. J Biol Chem 285(17): 13107-20. 2010
[http://dx.doi.org/10.1074/jbc.M110.100420] [PMID: 20178983]
[91]
Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F, Erdin S, et al. TFEB links autophagy to lysosomal biogenesis. Science 332(6036): 1429-33. 2011
[http://dx.doi.org/10.1126/science.1204592] [PMID: 21617040]
[92]
Area-Gomez E, Del Carmen Lara Castillo M, Tambini MD, Guardia-Laguarta C, de Groof AJ, Madra M, et al. Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. EMBO J 31(21): 4106-23. 2012
[http://dx.doi.org/10.1038/emboj.2012.202] [PMID: 22892566]
[93]
Chen Y, Zhu L, Ji L, Yang Y, Lu L, Wang X, et al. Silencing the ACAT1 Gene in Human SH-SY5Y Neuroblastoma Cells Inhibits the Expression of Cyclo-Oxygenase 2 (COX2) and Reduces β-Amyloid-Induced Toxicity Due to Activation of Protein Kinase C (PKC) and ERK. Med Sci Monit 24: 9007-18. 2018
[http://dx.doi.org/10.12659/MSM.912862] [PMID: 30541014]
[94]
Karch CM, Cruchaga C, Goate AM. Alzheimer’s disease genetics: from the bench to the clinic. Neuron 83(1): 11-26. 2014
[http://dx.doi.org/10.1016/j.neuron.2014.05.041] [PMID: 24991952]
[95]
Cacabelos R, Cacabelos P, Torrellas C, Tellado I, Carril JC. Pharmacogenomics of Alzheimer’s Disease: Novel Therapeutic Strategies for Drug Development. New York 2014; 323-556.
[96]
Cacabelos R, Torrellas C, Teijido O, Carril JC. Pharmacogenetic considerations in the treatment of Alzheimer’s disease. Pharmacogenomics 17(9): 1041-74. 2016
[http://dx.doi.org/10.2217/pgs-2016-0031] [PMID: 27291247]
[97]
Bai F, Yuan Y, Shi Y, Zhang Z. Multiple genetic imaging study of the association between cholesterol metabolism and brain functional alterations in individuals with risk factors for Alzheimer’s disease. Oncotarget 7(13): 15315-28. 2016
[http://dx.doi.org/10.18632/oncotarget.8100] [PMID: 26985771]
[98]
Cacabelos R. Pharmacogenomics and therapeutic prospects in Alzheimer’s disease. Expert Opin Pharmacother 6(12): 1967-87. 2005
[http://dx.doi.org/10.1517/14656566.6.12.1967] [PMID: 16197352]
[99]
Liu X, Yue C, Xu Z, Shu H, Pu M, Yu H, et al. Association study of candidate gene polymorphisms with amnestic mild cognitive impairment in a Chinese population. PLoS One 7(7)e41198 2012
[http://dx.doi.org/10.1371/journal.pone.0041198] [PMID: 22911757]
[100]
Picard C, Julien C, Frappier J, Miron J, Théroux L, Dea D, et al. United Kingdom Brain Expression Consortium and for the Alzheimer’s Disease Neuroimaging Initiative. Alterations in cholesterol metabolism-related genes in sporadic Alzheimer’s disease. Neurobiol Aging 66: 180.e1-9. 2018
[http://dx.doi.org/10.1016/j.neurobiolaging.2018.01.018] [PMID: 29503034]
[101]
Jones L, Holmans PA, Hamshere ML, Harold D, Moskvina V, Ivanov D, et al. Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer’s disease. PLoS One 5(11)e13950 2010
[http://dx.doi.org/10.1371/journal.pone.0013950] [PMID: 21085570]
[102]
Liu Q, An Y, Ma W, Feng L, Wang C, Lu Y, et al. Highcholesterol diet results in elevated amyloidβ and oxysterols in rats. Mol Med Rep 17(1): 1235-40. 2018
[PMID: 29115521]

Rights & Permissions Print Cite
Article Metrics
75
9
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy