ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD

Proceedings of the National Academy of Sciences of the United States of America

Volumn 107, Issue 7, 2010, Pages 3081-3086

  Bryleva, Elena Y ^a   Rogers, Maximillian A ^a   Chang, Catherine C Y ^a   Buen, Floyd ^a   Harris, Brent T ^b   Rousselet, Estelle ^c   Seidah, Nabil G ^c   Oddo, Salvatore ^d   Laferla, Frank M ^e   Spencer, Thomas A ^f   Hickey, William F ^b   Chang, Ta Yuan ^a  

^a DARTMOUTH MEDICAL SCHOOL   (United States)

^b DARTMOUTH HITCHCOCK MEDICAL CENTER   (United States)

^c CLIN RESEARCH INSTITUTE OF MONTREAL   (Canada)

^d UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO   (United States)

^e UNIVERSITY OF CALIFORNIA   (United States)

^f Dartmouth College   (United States)

Author keywords

Alzheimer disease; Cholesterol esterification; Lipid metabolism; Oxysterols

Indexed keywords

24 (S) HYDROXYCHOLESTEROL DERIVATIVE; 24 HYDROXYCHOLESTEROL; AMYLOID BETA PROTEIN; CHOLESTEROL ACYLTRANSFERASE; CHOLESTEROL ACYLTRANSFERASE 1; CHOLESTEROL ACYLTRANSFERASE 2; CHOLESTEROL DERIVATIVE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE; ISOENZYME; TAU PROTEIN; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BIOSYNTHESIS; BRAIN; COGNITIVE DEFECT; CONTROLLED STUDY; ENDOPLASMIC RETICULUM; GENE EXPRESSION; HIPPOCAMPUS; MOUSE; NERVE CELL CULTURE; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN CONTENT; STEROL SYNTHESIS;

ACETYL-COA C-ACETYLTRANSFERASE; ACYL COENZYME A; ALZHEIMER DISEASE; AMYLOID; ANIMALS; BRAIN; CHOLESTEROL; GENE SILENCING; HUMANS; HYDROXYCHOLESTEROLS; MICE; MICE, TRANSGENIC; MODELS, BIOLOGICAL;

MUS;

EID: 77649259094     PISSN: 00278424     EISSN: 10916490     Source Type: Journal    
DOI: 10.1073/pnas.0913828107     Document Type: Article

References (55)

1. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297:353-356.
2. Thinakaran G, Koo EH (2008) Amyloid precursor protein trafficking, processing, and function. J Biol Chem 283:29615-29619.
3. Wolozin B (2004) Cholesterol and the biology of Alzheimer's disease. Neuron 41: 7-10.
4. Jiang Q, et al. (2008) ApoE promotes the proteolytic degradation of Abeta. Neuron 58:681-693.
5. Wellington CL (2004) Cholesterol at the crossroads: Alzheimer's disease and lipid metabolism. Clin Genet 66:1-16.
6. Hartmann T (2001) Cholesterol, A beta and Alzheimer's disease. Trends Neurosci 24 (11, Suppl)S45-S48.
7. Dietschy JM, Turley SD (2004) Thematic review series: brain lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res 45:1375-1397.
8. Goldstein JL, DeBose-Boyd RA, Brown MS (2006) Protein sensors for membrane sterols. Cell 124:35-46.
9. Repa JJ, Mangelsdorf DJ (2000) The role of orphan nuclear receptors in the regulation of cholesterol homeostasis. Annu Rev Cell Dev Biol 16:459-481.
10. Beaven SW, Tontonoz P (2006) Nuclear receptors in lipid metabolism: targeting the heart of dyslipidemia. Annu Rev Med 57:313-329.
11. Wang N, et al. (2008) ATP-binding cassette transporters G1 and G4 mediate cholesterol and desmosterol efflux to HDL and regulate sterol accumulation in the brain. FASEB J 22:1073-1082.
12. Tarr PT, Edwards PA (2008) ABCG1 and ABCG4 are coexpressed in neurons and astrocytes of the CNS and regulate cholesterol homeostasis through SREBP-2. J Lipid Res 49:169-182.
13. Russell DW, Halford RW, Ramirez DM, Shah R, Kotti T (2009) Cholesterol 24-hydroxylase: an enzyme of cholesterol turnover in the brain. Annu Rev Biochem 78: 1017-1040.
14. Lütjohann D, et al. (1996) Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation. Proc Natl Acad Sci USA 93:9799-9804.
15. Song BL, Javitt NB, DeBose-Boyd RA (2005) Insig-mediated degradation of HMG CoA reductase stimulated by lanosterol, an intermediate in the synthesis of cholesterol. Cell Metab 1:179-189.
16. Wang Y, Muneton S, Sjövall J, Jovanovic JN, Griffiths WJ (2008) The effect of 24S-hydroxycholesterol on cholesterol homeostasis in neurons: quantitative changes to the cortical neuron proteome. J Proteome Res 7:1606-1614.
17. Brown J, 3rd, et al. (2004) Differential expression of cholesterol hydroxylases in Alzheimer's disease. J Biol Chem 279:34674-34681.
18. Heverin M, et al. (2004) Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease. J Lipid Res 45:186-193.
19. Chang TY, Li BL, Chang CC, Urano Y (2009) Acyl-coenzyme A:cholesterol acyltransferases. Am J Physiol Endocrinol Metab 297:E1-E9.
20. Hutter-Paier B, et al. (2004) The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer's disease. Neuron 44:227-238.
21. Huttunen HJ, Kovacs DM (2008) ACAT as a drug target for Alzheimer's disease. Neurodegener Dis 5:212-214.
22. Meiner V, et al. (1997) Tissue expression studies on the mouse acyl-CoA: cholesterol acyltransferase gene (Acact): findings supporting the existence of multiple cholesterol esterification enzymes in mice. J Lipid Res 38:1928-1933.
23. Anderson RA, et al. (1998) Identification of a form of acyl-CoA:cholesterol acyltransferase specific to liver and intestine in nonhuman primates. J Biol Chem 273: 26747-26754.
24. Morrissette DA, Parachikova A, Green KN, LaFerla FM (2009) Relevance of transgenic mouse models to human Alzheimer disease. J Biol Chem 284:6033-6037.
25. Cai D, et al. (2003) Presenilin-1 regulates intracellular trafficking and cell surface delivery of beta-amyloid precursor protein. J Biol Chem 278:3446-3454.
26. Weidemann A, et al. (1989) Identification, biogenesis, and localization of precursors of Alzheimer's disease A4 amyloid protein. Cell 57:115-126.
27. Oltersdorf T, et al. (1990) The Alzheimer amyloid precursor protein. Identification of a stable intermediate in the biosynthetic/degradative pathway. J Biol Chem 265: 4492-4497.
28. Buxbaum JD, et al. (1990) Processing of Alzheimer beta/A4 amyloid precursor protein: modulation by agents that regulate protein phosphorylation. Proc Natl Acad Sci USA 87:6003-6006.
29. Slunt HH, et al. (1994) Expression of a ubiquitous, cross-reactive homologue of the mouse beta-amyloid precursor protein (APP). J Biol Chem 269:2637-2644.
30. Du P, et al. (2007) Dominance of amyloid precursor protein sequence over host cell secretases in determining beta-amyloid profiles studies of interspecies variation and drug action by internally standardized immunoprecipitation/mass spectrometry. J Pharmacol Exp Ther 320:1144-1152.
31. Muhammad A, et al. (2008) Retromer deficiency observed in Alzheimer's disease causes hippocampal dysfunction, neurodegeneration, and Abeta accumulation. Proc Natl Acad Sci USA 105:7327-7332.
32. Liu B, et al. (2009) Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1-/- mouse. Proc Natl Acad Sci USA 106:2377-2382.
33. Liu J, Chang CC, Westover EJ, Covey DF, Chang TY (2005) Investigating the allosterism of acyl-CoA:cholesterol acyltransferase (ACAT) by using various sterols: in vitro and intact cell studies. Biochem J 391:389-397.
34. Kim WS, et al. (2007) Role of ABCG1 and ABCA1 in regulation of neuronal cholesterol efflux to apolipoprotein E discs and suppression of amyloid-beta peptide generation. J Biol Chem 282:2851-2861.
35. Huttunen HJ, et al. (2009) Inhibition of acyl-coenzyme A: cholesterol acyl transferase modulates amyloid precursor protein trafficking in the early secretory pathway. FASEB J 23:3819-3828.
36. Hofmann K (2000) A superfamily of membrane-bound O-acyltransferases with implications for wnt signaling. Trends Biochem Sci 25:111-112.
37. Homan R, Hamelehle KL (2001) Influence of membrane partitioning on inhibitors of membrane-bound enzymes. J Pharm Sci 90:1859-1867.
38. Rockenstein E, et al. (2006) Cerebrolysin decreases amyloid-beta production by regulating amyloid protein precursor maturation in a transgenic model of Alzheimer's disease. J Neurosci Res 83:1252-1261.
39. Rockenstein E, et al. (2007) Effects of Cerebrolysin on neurogenesis in an APP transgenic model of Alzheimer's disease. Acta Neuropathol 113:265-275.
40. Beel AJ, et al. (2008) Structural studies of the transmembrane C-terminal domain of the amyloid precursor protein (APP): does APP function as a cholesterol sensor? Biochemistry 47:9428-9446.
41. Epand RM (2008) Proteins and cholesterol-rich domains. Biochim Biophys Acta 1778: 1576-1582.
42. Tabas I, Weiland DA, Tall AR (1986) Inhibition of acyl coenzyme A:cholesterol acyl transferase in J774 macrophages enhances down-regulation of the low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl-coenzyme A reductase and prevents low density lipoprotein-induced cholesterol accumulation. J Biol Chem 261: 3147-3155.
43. Scheek S, Brown MS, Goldstein JL (1997) Sphingomyelin depletion in cultured cells blocks proteolysis of sterol regulatory element binding proteins at site 1. Proc Natl Acad Sci USA 94:11179-11183.
44. Björkhem I (2009) Are side-chain oxidized oxysterols regulators also in vivo? J Lipid Res 50 (Suppl):S213-S218.
45. Lund EG, et al. (2003) Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover. J Biol Chem 278:22980-22988.
46. Kotti TJ, Ramirez DM, Pfeiffer BE, Huber KM, Russell DW (2006) Brain cholesterol turnover required for geranylgeraniol production and learning in mice. Proc Natl Acad Sci USA 103:3869-3874.
47. Halford RW, Russell DW (2009) Reduction of cholesterol synthesis in the mouse brain does not affect amyloid formation in Alzheimer's disease, but does extend lifespan. Proc Natl Acad Sci USA 106:3502-3506.
48. Hudry E, et al. (2009) Adeno-associated virus gene therapy with cholesterol 24-hydroxylase reduces the amyloid pathology before or after the onset of amyloid plaques in mouse models of Alzheimer's disease. Mol Ther.
49. Brown AJ, Jessup W (2009) Oxysterols: sources, cellular storage and metabolism, and new insights into their roles in cholesterol homeostasis. Mol Aspects Med 30:111-122.
50. Warner GJ, Stoudt G, Bamberger M, Johnson WJ, Rothblat GH (1995) Cell toxicity induced by inhibition of acyl coenzyme A:cholesterol acyltransferase and accumulation of unesterified cholesterol. J Biol Chem 270:5772-5778.
51. Tabas I (2002) Consequences of cellular cholesterol accumulation: basic concepts and physiological implications. J Clin Invest 110:905-911.
52. Sun Y, Yao J, Kim TW, Tall AR (2003) Expression of liver X receptor target genes decreases cellular amyloid beta peptide secretion. J Biol Chem 278:27688-27694.
53. Meiner VL, et al. (1996) Disruption of the acyl-CoA:cholesterol acyltransferase gene in mice: evidence suggesting multiple cholesterol esterification enzymes in mammals. Proc Natl Acad Sci USA 93:14041-14046.
54. Buhman KK, et al. (2000) Resistance to diet-induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice. Nat Med 6:1341-1347.
55. Oddo S, et al. (2003) Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409-421.