- Alzheimer’s disease
- Endoplasmic reticulum
Accumulation of β-amyloid peptide (Aβ) in the brain regions responsible for memory and cognitive functions is a neuropathological hallmark of Alzheimer’s disease. Cholesterol may be involved in many aspects of Aβmetabolism. It affects generation, aggregation and clearance of Aβin the brain. Not only the amount but also the distribution of cholesterol within cells appears to modulate Aβbiogenesis. ACAT is an enzyme that regulates subcellular cholesterol distribution by converting membrane cholesterol to cholesteryl esters for storage and transport. We have used various cell- and animal based models to show that inhibition of ACAT strongly reduces Aβgeneration and protects from amyloid pathology. Here, we discuss data supporting ACAT inhibition as a strategy to treat Alzheimer’s disease.
Copyright © 2008 S. Karger AG, Basel
- Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA: Statins and the risk of dementia. Lancet 2000;356:1627–1631.
- 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 2000;57:1439–1443.
- Huttunen HJ, Kovacs DM: Cholesterol and β-amyloid; in Sisodia SS, Tanzi RE (eds): Alzheimer’s Disease. Advances in Genetics, Molecular and Cellular Biology. New York, Springer, 2007, pp 93–111.
- Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, et al: Inflammation and Alzheimer’s disease. Neurobiol Aging 2000;21:383–421.
- Kwak B, Mulhaupt F, Myit S, Mach F: Statins as a newly recognized type of immunomodulator. Nat Med 2000;6:1399–1402.
- Menge T, Hartung HP, Stuve O: Statins – A cure-all for the brain? Nat Rev Neurosci 2005;6:325–331.
- Cordle A, Landreth G: 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors attenuate beta-amyloid-induced microglial inflammatory responses. J Neurosci 2005;25:299–307.
- Pedrini S, Carter TL, Prendergast G, Petanceska S, Ehrlich ME, Gandy S: Modulation of statin-activated shedding of Alzheimer APP ectodomain by ROCK. PLoS Med 2005;2:e18.
- Chang TY, Chang CC, Cheng D: Acyl-coenzyme A:cholesterol acyltransferase. Annu Rev Biochem 1997;66:613–638.
- Buhman KF, Accad M, Farese RV: Mammalian acyl-CoA:cholesterol acyltransferases. Biochim Biophys Acta 2000;1529:142–154.
- Chang TY, Chang CC, Lin S, Yu C, Li BL, Miyazaki A: Roles of acyl-coenzyme A:cholesterol acyltransferase-1 and -2. Curr Opin Lipidol 2001;12:289–296.
- Puglielli L, Konopka G, Pack-Chung E, Ingano LA, Berezovska O, Hyman BT, Chang TY, Tanzi RE, Kovacs DM: Acyl-coenzyme A:cholesterol acyltransferase modulates the generation of the amyloid beta-peptide. Nat Cell Biol 2001;3:905–912.
- Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE: Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet 2007;39:17–23.
- Wollmer MA, Streffer JR, Tsolaki M, Gri-maldi LM, Lutjohann D, Thal D, Von Bergmann K, Nitsch RM, Hock C, Papassotiropoulos A: Genetic association of acyl-coenzyme A:cholesterol acyltransferase with cerebrospinal fluid cholesterol levels, brain amyloid load, and risk for Alzheimer’s disease. Mol Psychiatry 2003;8:635–638.
- Giovannoni MP, Piaz VD, Vergelli C, Barlocco D: Selective ACAT inhibitors as promising antihyperlipidemic, antiathero-sclerotic and anti-Alzheimer drugs. Mini Rev Med Chem 2003;3:576–584.
- Hutter-Paier B, Huttunen HJ, Puglielli L, Eckman CB, Kim DY, Hofmeister A, Moir RD, Domnitz SB, Frosch MP, Windisch M, Kovacs DM: The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer’s disease. Neuron 2004;44:227–238.
- Alegret M, Llaverias G, Silvestre JS: Acyl coenzyme A:cholesterol acyltransferase inhibitors as hypolipidemic and antiatherosclerotic drugs. Methods Find Exp Clin Pharmacol 2004;26:563–586.
- Huttunen HJ, Greco C, Kovacs DM: Knockdown of ACAT-1 reduces amyloidogenic processing of APP. FEBS Lett 2007;581:1688–1692.
Dr. Dora M. Kovacs
Neurobiology of Disease Laboratory, Genetics and Aging Research Unit
Massachusetts General Hospital, Harvard Medical School
114 16th St., Charlestown, MA 02129 (USA)
Tel. +1 617 726 3668, Fax +1 617 724 1823, E-Mail Dora_Kovacs@hms.harvard.edu
Published online: March 6, 2008
Number of Print Pages : 3
Number of Figures : 0, Number of Tables : 0, Number of References : 18
Vol. 5, No. 3-4, Year 2008 (Cover Date: March 2008)
Journal Editor: Nitsch R.M. (Zürich), Hock C. (Zürich)
ISSN: 1660–2854 (Print), eISSN: 1660–2862 (Online)
For additional information: http://www.karger.com/NDD
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