Regulation of cerebral cholesterol metabolism in Alzheimer disease

Journal of Investigative Medicine

Volumn 60, Issue 3, 2012, Pages 576-582

  Reiss, Allison B ^a   Voloshyna, Iryna ^a  

^a WINTHROP UNIVERSITY HOSPITAL   (United States)

Author keywords

A amyloid peptide; ABCA1; Alzheimer disease; Amyloid precursor protein; Apolipoprotein E; LXR; Oxysterol

Indexed keywords

ABC TRANSPORTER A1; ACYL COENZYME A; AMYLOID BETA PROTEIN; AMYLOID BETA PROTEIN[1-40]; AMYLOID BETA PROTEIN[1-42]; ANTIINFLAMMATORY AGENT; ANTILIPEMIC AGENT; ANTIOXIDANT; APOLIPOPROTEIN E; CHOLESTEROL; CHOLESTEROL ACYLTRANSFERASE; CHOLESTEROL ACYLTRANSFERASE INHIBITOR; CP 113818; GAMMA SECRETASE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LIPID; LIVER X RECEPTOR; OXYSTEROL; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; AMYLOIDOSIS; ANTICOAGULATION; ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; ARTICLE; CHOLESTEROL BLOOD LEVEL; CHOLESTEROL METABOLISM; HUMAN; IN VITRO STUDY; IN VIVO STUDY; METABOLIC REGULATION; NEUROPATHOLOGY; NONHUMAN;

ANIMALIA;

ALZHEIMER DISEASE; AMYLOID BETA-PEPTIDES; ANIMALS; BRAIN; CHOLESTEROL; HUMANS; LIPID METABOLISM; SIGNAL TRANSDUCTION;

EID: 84860832039     PISSN: 17088267     EISSN: 17088267     Source Type: Journal    
DOI: 10.2310/JIM.0b013e318246d973     Document Type: Article

References (107)

1. Blennow K, de Leon MJ, Zetterberg H. Alzheimer's disease. Lancet. 2006;368:387-403. (Pubitemid 44108123)
2. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239-259.
3. Auld DS, Kornecook TJ, Bastianetto S, et al. Alzheimer's disease and the basal forebrain cholinergic system: Relations to beta-amyloid peptides, cognition, and treatment strategies. Prog Neurobiol. 2002;68:209-245. (Pubitemid 35346805)
4. Alzheimer's Association. Alzheimer's disease facts and figures. Alzheimers Dement. 2011;7(2):208-244.
5. Canepa E, Borghi R, Vina J, et al Cholesterol and amyloid-A: Evidence for a cross-talk between astrocytes and neuronal cells. J Alzheimer's Dis. 2011;25(4):645-653.
6. Rebeck GW, Reiter JS, Strickland DK, et al. Apolipoprotein E in sporadic Alzheimer's disease: Allelic variation and receptor interactions. Neuron. 1993;11:575-580. (Pubitemid 23321768)
7. Burns M, Duff K. Cholesterol in Alzheimer's disease and tauopathy. Ann NY Acad Sci. 2002;977:367-375. (Pubitemid 35418177)
8. Poirier J. Apolipoprotein E, cholesterol transport and synthesis in sporadic Alzheimer's disease. Neurobiol Aging. 2005;26:355-361. (Pubitemid 40082719)
9. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics. Science. 2002;297:353-356. (Pubitemid 34790756)
10. Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med. 2010;362:329-344.
11. Jellinger KA. The neuropathological diagnosis of Alzheimer disease. J Neural Transm Suppl. 1998;53:97-118. (Pubitemid 28361772)
12. Selkoe DJ, Schenk D. Alzheimer's disease: Molecular understanding predicts myloid-based therapeutics. Annu Rev Pharmacol Toxicol. 2003;43:545-584. (Pubitemid 37372653)
13. Yan R, Bienkowski MJ, Shuck ME, et al. Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature. 1999;402:533-537.
14. Edbauer D, Winkler E, Regula JT, et al. Reconstitution of gamma-secretase activity. Nat Cell Biol. 2003;5:486-488.
15. Selkoe D, Kopan R. Notch and presenilin: Regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci. 2003;26:565-597. (Pubitemid 37064944)
16. Ghosh AK, Gemma S, Tang J. Beta-secretase as a therapeutic target for Alzheimer's disease. Neurotherapeutics. 2008;5:399-408. (Pubitemid 351952491)
17. Iwatsubo T, Odaka A, Suzuki N, et al. Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: Evidence that an initially deposited species is A beta 42(43). Neuron. 1994;13:45-53.
18. Verdile G, Fuller S, Atwood CS, et al. The role of beta amyloid in Alzheimer's disease: Still a cause of everything or the only one who got caught? Pharmacol Res. 2004;50:397-409. (Pubitemid 39078531)
19. Lichtenthaler SF. Alpha-secretase in Alzheimer's disease: Molecular identity, regulation and therapeutic potential. J Neurochem. 2011;116(1):10-21.
20. Lin LF, Luo HM. Screening of treatment targets for Alzheimer's disease from the molecular mechanisms of impairment by A-amyloid aggregation and tau hyperphosphorylation. Neurosci Bull. 2011;27(1):53-60.
21. Mouritsen OG, Zuckermann MJ. What's so special about cholesterol? Lipids. 2004;39:1101-1113. (Pubitemid 40136615)
22. Dietschy JM, Turley SD. Cholesterol metabolism in the brain. Curr Opin Lipidol. 2001;12:105-112. (Pubitemid 32242918)
23. Morell P, Jurevics H. Origin of cholesterol in myelin. Neurochem Res. 1996;21:463-470. (Pubitemid 26159264)
24. Vance JE, Hayashi H, Karten B. Cholesterol homeostasis in neurons and glial cells. Semin Cell Dev Biol. 2005;16:193-212. (Pubitemid 40432121)
25. Dietschy JM. Central nervous system: Cholesterol turnover, brain development and neurodegeneration. Biol Chem. 2009;390:287-293.
26. Bjorkhem I, Meaney S. Brain cholesterol: Long secret life behind a barrier. Arterioscler Thromb Vasc Biol. 2004;24:806-815. (Pubitemid 38620856)
27. Andersson M, Elmberger PG, Edlund C, et al. Rates of cholesterol, ubiquinone, dolichol and dolichyl-P biosynthesis in rat brain slices. FEBS Lett. 1990;269:15-18. (Pubitemid 20245305)
28. Nieweg K, Schaller H, Pfrieger FW. Marked differences in cholesterol synthesis between neurons and glial cells from postnatal rats. J Neurochem. 2009;109:125-134.
29. Mahley RW. Apolipoprotein E: Cholesterol transport protein with expanding role in cell biology. Science. 1988;240:622-630.
30. Anstey KJ, Lipnicki DM, Low LF. Cholesterol as a risk factor for dementia and cognitive decline: A systematic review of prospective studies with meta-analysis. Am J Geriatr Psychiatry. 2008;16:343-354.
31. Wolozin B, Kellman W, Ruosseau P, et al. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000;57:1439-1443.
32. Solomon A, Kivipelto M, Wolozin B, et al. Midlife serum cholesterol and increased risk of Alzheimer's and vascular dementia three decades later. Dement Geriatr Cogn Disord. 2009;28(1):75-80.
33. Mielke MM, Zandi PP, Shao H, et al. The 32-year relationship between cholesterol and dementia from midlife to late life. Neurology. 2010;75(21):1888-1895.
34. Jick H, Zornberg GL, Jick SS, et al. Statins and the risk of dementia. Lancet. 2000;356:1627-1631.
35. Rockwood K, Kirkland S, Hogan DB, et al. Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch Neurol. 2002;59:223-227. (Pubitemid 34240938)
36. Pasternak RC, Smith SC Jr, Bairey-Merz CN, et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol. 2002;40:567-572. (Pubitemid 34833176)
37. Mihos CG, Santana O. Pleiotropic effects of the HMG-CoA reductase inhibitors. Int J Gen Med. 2011;4:261-271.
38. Bellosta S, Ferri N, Bernini F, et al. NonYlipid-related effects of statins. Ann Med. 2000;32:164-176.
39. Ostrowski SM, Wilkinson BL, Golde TE, et al. Statins reduce amyloid-beta production through inhibition of protein isoprenylation. J Biol Chem. 2007;282:26832-26844. (Pubitemid 47501902)
40. Biondi E. Prescription of lipophilic statins to Alzheimer's disease patients: Some controversies to consider. Neurol Sci. 2011;32:195-201.
41. Zandi PP, Sparks DL, Khachaturian AS, et al. Do statins reduce risk of incident dementia and Alzheimer disease? The Cache County Study. Arch Gen Psychiatry. 2005;62:217-224. (Pubitemid 40189139)
42. Rea TD, Breitner JC, Psaty BM, et al. Statin use and the risk of incident dementia: The Cardiovascular Health Study. Arch Neurol. 2005;62:1047-1051. (Pubitemid 41043724)
43. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): A randomised controlled trial. Lancet. 2002;360:1623-1630. (Pubitemid 35379733)
44. Haag MD, Hofman A, Koudstaal PJ, et al. Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study. J Neurol Neurosurg Psychiatry. 2009;80:13-17.
45. Simons M, Keller P, De Strooper B, et al. Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci. 1998;95:6460-6464. (Pubitemid 28249035)
46. Frears ER, Stephens DJ, Walters CE, et al. The role of cholesterol in the biosynthesis of [beta]-amyloid. Neuroreport. 1999;10(8):1699-1705.
47. Harris JR. Cholesterol binding to amyloid fibrils: A TEM study. Micron. 2008;39:1192-1196.
48. Beel AJ, Sakakura M, Barrett PJ, et al. Direct binding of cholesterol to the amyloid precursor protein: An important interaction in lipid-Alzheimer's disease relationships? Biochim Biophys Acta. 2010;1801(8):975-982.
49. Ehehalt R, Keller P, Haass C, et al. Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts. J Cell Biol. 2003;160:113-123. (Pubitemid 36091721)
50. Refolo LM, Malester B, LaFrancois J, et al. Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol Dis. 2000;4:321-331.
51. Burns M, Gaynor K, Olm V, et al. Presenilin redistribution associated with aberrant cholesterol transport enhances beta-amyloid production in vivo. J Neurosci. 2003;23:5645-5649. (Pubitemid 36807842)
52. Hooijmans CR, Rutters F, Dederen PJ, et al. Changes in cerebral blood volume and amyloid pathology in aged Alzheimer APP/PS1 mice on a docosahexaenoic acid (DHA) diet or cholesterol enriched Typical Western Diet (TWD). Neurobiol Dis. 2007;28:16-29. (Pubitemid 47432903)
53. Fitz NF, Cronican A, Pham T, et al. LXR agonist treatment ameliorates amyloid pathology and memory deficits caused by high fat diet in APP23 mice. J Neurosci. 2010;30(20):6862-6872.
54. Sparks DL, Kuo YM, Roher A, et al. Alterations of Alzheimer's disease in the cholesterol-fed rabbit, including vascular inflammation. Preliminary observations. Ann NY Acad Sci. 2000;903:335-344. (Pubitemid 30251574)
55. Ghribi O, Golovko MY, Larsen B, et al. Deposition of iron and beta-amyloid plaques is associated with cortical cellular damage in rabbits fed with long-term cholesterol-enriched diets, J Neurochem. 2006;99:438-449. (Pubitemid 44477201)
56. Ghribi O, Larsen B, Schrag M, et al. High cholesterol content in neurons increases BACE, A-amyloid, and phosphorylated tau levels in rabbit hippocampus. Exp Neurol. 2006;200:460-467. (Pubitemid 44107924)
57. Jaya Prasanthi RP, Schommer E, Thomasson S, et al. Regulation of beta-amyloid levels in the brain of cholesterol-fed rabbit, a model system for sporadic Alzheimer's disease. Mech Ageing Dev. 2008;129:649-655.
58. Fassbender K, Simons M, Bergmann C, 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 U S A. 2001;98:5856-5861. (Pubitemid 32435732)
59. Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997;278: 1349-1356. (Pubitemid 27449696)
60. Weisgraber KH. Apolipoprotein E: Structure-function relationships. Adv Protein Chem. 1994;45:249-302. (Pubitemid 24139890)
61. Schipper HM. Apolipoprotein E: Implications for AD neurobiology, epidemiology and risk assessment. Neurobiology of Aging. 2011;32(5):778-790.
62. Xu Q, Bernardo A, Walker D, et al. Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus. J Neurosci. 2006;26:4985-4994. (Pubitemid 44315280)
63. Namba Y, Tomonaga M, Kawasaki H, et al. Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt-Jakob disease. Brain Res. 1991;541:163-166.
64. Sheng JG, Mrak RE, Griffin WS. Apolipoprotein E distribution among different plaque types in Alzheimer's disease: Implications for its role in plaque progression. Neuropathol Appl Neurobiol. 1996;22:334-341. (Pubitemid 26278837)
65. Holtzman DM, Bales KR, Tenkova T, et al. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2000;97:2892-2897. (Pubitemid 30159268)
66. Carter DB, Dunn E, McKinley DD, et al. Human apolipoprotein E4 accelerates beta-amyloid deposition in APPsw transgenic mouse brain. Ann Neurol. 2001;50:468-475. (Pubitemid 32938891)
67. Bales KR, Verina T, Cummins DJ, et al. Apolipoprotein E is essential for amyloid deposition in the APP (V717F) transgenic mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 1999;96: 15233-15238. (Pubitemid 30019795)
68. Wahrte SE, Holtzman DM. Apolipoprotein E, amyloid b peptide, and Alzheimer's disease. In: Dawbarn D, Allen SJ, eds. Neurobiology of Alzheimer's Disease. New York, NY: Oxford University Press, Inc; 2007:161-172.
69. Deane R, Sagare A, Hamm K, et al. ApoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Invest. 2008;118:4002-4013.
70. Bjorkhem I. Rediscovery of cerebrosterol. Lipids. 2007;42:5-14. (Pubitemid 46490739)
71. Meaney S, Hassan M, Sakinis A, et al. Evidence that the major oxysterols in human circulation originate from distinct pools of cholesterol: A stable isotope study. J Lipid Res. 2001;42:70-78. (Pubitemid 32142861)
72. Lund EG, Guileyardo JM. Russell DW. cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain. Proc Natl Acad Sci U S A. 1999;96:7238-7243. (Pubitemid 29299645)
73. Bjorkhem I, Lutjohann D, Diczfalusy U, et al. Cholesterol homeostasis in human brain: Turnover of 24s-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation. J Lipid Res. 1998;39:1594-1600. (Pubitemid 28377923)
74. 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. 2004;45:1375-1397. (Pubitemid 39022664)
75. Andersson S, Davis DL, Dahlback H, et al. Cloning, structure, and expression of the mitochondrial cytochrome p-450 sterol 26-hydroxylase, a bile acid biosynthetic enzyme. J Biol Chem. 1989;264:8222-8229. (Pubitemid 19137311)
76. Reiss AB, Martin KO, Rojer DE, et al. Sterol 27-hydroxylase: Expression in human arterial endothelium. J Lipid Res. 1997;38:1254-1260. (Pubitemid 27281819)
77. Heverin M, Meaney S, Lutjohann D, et al. Crossing the barrier: Net flux of 27-hydroxycholesterol into the human brain. J Lipid Res. 2005;46:1047-1052.
78. Sharma S, Prasanthi RPJ, Schommer E, et al. Hypercholesterolemia-induced Abeta accumulation in rabbit brain is associated with alteration in IGF-1 signaling. Neurobiol Dis. 2008;32:426-432.
79. Bjorkhem I, Heverin M, Leoni V, et al. Oxysterols and Alzheimer's disease. Acta Neurol Scand Suppl. 2006;185:43-49. (Pubitemid 44015224)
80. Brown J 3rd, Theisler C, Silberman S, et al. Differential expression of cholesterol hydroxylases in Alzheimer's disease. J Biol Chem. 2004;279:34674-34681. (Pubitemid 39318097)
81. Kim WS, Chan SL, Hill AF, et al. Impact of 27-hydroxycholesterol on amyloid-beta peptide production and ATP-binding cassette transporter expression in primary human neurons. J Alzheimers Dis. 2009;16(1):121-131.
82. Prasanthi JRP, Huls A, Thomasson S, et al. Differential effects of 24-hydroxycholesterol and 27-hydroxycholesterol on beta-amyloid precursor protein levels and processing in human neuroblastoma SH-SY5-cells. Mol Neurodegener. 2009;4:1.
83. Halford RW, Russell DW. 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 U S A. 2009;106:3502-3506.
84. Xie C, Lund EG, Turley SD, et al. Quantitation of two pathways for cholesterol excretion from the brain in normal mice and mice with neurodegeneration. J Lipid Res. 2003;44:1780-1789. (Pubitemid 37185890)
85. Voloshyna I, Reiss AB. The ABC transporters in lipid flux and atherosclerosis. Prog Lipid Res. 2011;50(3):213-224.
86. Schmitz G, Langmann T. Structure, function and regulation of the ABC1 gene production. Curr Opin Lipidol. 2001;12:129-140. (Pubitemid 32242920)
87. Wang N, Tall AR. Regulation and mechanisms of ATP-binding cassette transporter A1-mediated cellular cholesterol efflux. Arterioscler Thromb Vasc Biol. 2003;23:1178-1184. (Pubitemid 36871270)
88. Koldamova R, Fitz NF, Lefterov I. The role of ATP-binding cassette transporter A1 in Alzheimer's disease and neurodegeneration. Biochim Biophys Acta. 2010;1801(8):824-830.
89. Kim WS, Hill AF, Fitzgerald ML, et al. Wild type and tangier disease ABCA1 mutants modulate cellular amyloid-A production independent of cholesterol efflux activity. J Alzheimers Dis. 2011;27(2):441-452.
90. Wahrle SE, Jiang H, Parsadanian M, et al. ABCA1 is required for normal central nervous system APOE levels and for lipidation of astrocyte-secreted APOE. J Biol Chem. 2004;279:40987-40993. (Pubitemid 39287699)
91. Wahrle SE, Jiang H, Parsadanian M, et al. Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J Clin Invest. 2008;118(2):671-682. (Pubitemid 351206556)
92. Loane DJ, Washington PM, Vardanian L, et al. Modulation of ABCA1 by an LXR agonist reduces beta-amyloid levels and improves outcome after traumatic brain injury. J Neurotrauma. 2011;28(2):225-236.
93. Terwel D, Steffensen KR, Verghese PB, et al. Critical role of astroglial apolipoprotein E and liver X receptor expression for microglial AA phagocytosis. J Neurosci. 2011;31(19): 7049-7059.
94. Schweinzer C, Kober A, Lang I, et al. Processing of endogenous AAPP in blood-brain barrier endothelial cells is modulated by liver-X receptor agonists and altered cellular cholesterol homeostasis. J Alzheimers Dis. 2011;27(2):341-360.
95. Donkin JJ, Stukas S, Hirsch-Reinshagen V, et al. ATP-binding cassette transporter A1 mediates the beneficial effects of the liver X receptor agonist GW3965 on object recognition memory and amyloid burden in amyloid precursor protein/presenilin 1 mice. J Biol Chem. 2010;285(44):34144-34154.
96. Cronican AA, Fitz NF, Pham T, et al. Proton pump inhibitor lansoprazole is a nuclear liver X receptor agonist. Biochem Pharmacol. 2010;79(9):1310-1316.
97. Chan SL, Kim WS, Kwok JB, et al. ATP-binding cassette transporter A7 regulates processing of amyloid precursor protein in vitro. J Neurochem. 2008;106:793-804.
98. Chang TY, Chang CCY, Cheng D. Acyl-coenzyme A: Cholesterol acyltransferase. Annu Rev Biochem. 1997;66:613-633.
99. Huttunen HJ, Peach C, Bhattacharyya R, et al. Inhibition of acyl-coenzyme A: Cholesterol acyl transferase modulates amyloid precursor protein trafficking in the early secretory pathway. FASEB J. 2009;23:3819-3828.
100. Hutter-Paier B, Huttunen HJ, Puglielli L, et al. The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer's disease. Neuron. 2004;44:227-238. (Pubitemid 39346248)
101. Shepardson NE, Shankar GM, Selkoe DJ. Cholesterol level and statin use in Alzheimer Disease: II. Review of human trials and recommendations. Arch Neurol. 2011;68:1385-1392.
102. Lee CY, Tse W, Landreth GE. ApoE promotes AA trafficking and degradation by modulating microglial cholesterol levels. J Biol Chem. 2011 Nov 30. [Epub ahead of print].
103. Di Paolo G, Kim TW. Linking lipids to Alzheimer's disease: Cholesterol and beyond. Nat Rev Neurosci. 2011;12(5):284-296. 103. Ariga T, Miyatake T, Yu RK. Role of proteoglycans and glycosaminoglycans in the pathogenesis of Alzheimer's disease and related disorders: Amyloidogenesis and therapeutic strategies;a review. Journal of Neuroscience Research. 2010;88(11): 2303-2315.
104. Ostrowitzki S, Deptula D, Thurfjell L, et al. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol. 2011 Oct 10. [Epub ahead of print].
105. Iqbal K, Grundke-Iqbal I. Opportunities and challenges in developing Alzheimer disease therapeutics. Acta Neuropathol. 2011;122(5):543-549.
106. Ben Halima S, Rajendran L. Membrane anchored and lipid raft targeted A-secretase inhibitors for Alzheimer's disease therapy. J Alzheimers Dis. 2011;24(suppl 2):143-152.
107. Rajendran L, Schneider A, Schlechtingen G, et al. Efficient inhibition of the Alzheimer's disease beta-secretase by membrane targeting. Science. 2008;320(5875):520-523. (Pubitemid 351590663)