title: Modulation of cholesterol, farnesylpyrophosphate, and geranylgeranylpyrophosphate in neuroblastoma SH-SY5Y-APP695 cells: impact on amyloid beta-protein production.
abstract: There is keen interest in the role of the isoprenoids farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP) in protein prenylation and cell function in Alzheimer's disease (AD). We recently reported elevated FPP and GGPP brain levels and increased gene expression of FPP synthase (FPPS) and GGPP synthase (GGPPS) in the frontal cortex of AD patients. Cholesterol levels and gene expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase were similar in AD and control samples, suggesting that homeostasis of FPP and GGPP but not cholesterol is specifically targeted in brain tissue of AD patients (Neurobiol Dis 2009 35:251-257). In the present study, it was determined if cellular levels of FPP, GGPP, and cholesterol affect beta-amyloid (Abeta) abundance in SH-SY5Y cells, expressing human APP695. Cells were treated with different inhibitors of the mevalonate/isoprenoid/cholesterol pathway. FPP, GGPP, cholesterol, and Abeta(1-40) levels were determined, and activities of farnesyltransferase and geranylgeranyltransferase I were measured. Inhibitors of different branches of the mevalonate/isoprenoid/cholesterol pathway as expected reduced cholesterol and isoprenoid levels in neuroblastoma cells. Abeta(1-40) levels were selectively reduced by cholesterol synthesis inhibitors but not by inhibitors of protein isoprenylation, indicating that changes in cholesterol levels per se and not isoprenoid levels account for the observed modifications in Abeta production.
authors.affiliation: Department of Pharmacology, Goethe University, Campus Riedberg, Biocenter N260, Max-von-Laue-St. 9, 60438, Frankfurt, Germany.
authors.forename: Gero P
authors.initials: GP
authors.lastname: Hooff
authors.forename: Imke
authors.initials: I
authors.lastname: Peters
authors.forename: W Gibson
authors.initials: WG
authors.lastname: Wood
authors.forename: Walter E
authors.initials: WE
authors.lastname: Müller
authors.forename: Gunter P
authors.initials: GP
authors.lastname: Eckert
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000736:Androstenes; D000818:Animals; D000924:Anticholesteremic Agents / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D008798:Mevalonic Acid / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000378:metabolism*; D012717:Sesquiterpenes / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000736:Androstenes; D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; C004808:farnesyl pyrophosphate; D002784:Cholesterol; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid
references.citation: J Biol Chem. 2000 Jan 7;275(1):423-8
references.pmid: 10617634
references.citation: Neurobiol Dis. 2006 May;22(2):209-22
references.pmid: 16406223
references.citation: J Cell Sci. 2007 Jan 15;120(Pt 2):205-12
references.pmid: 17215449
references.citation: Trends Neurosci. 2002 Apr;25(4):191-9
references.pmid: 11998687
references.citation: Clin Biochem. 2007 Jun;40(9-10):575-84
references.pmid: 17467679
references.citation: Brain Pathol. 1999 Jan;9(1):133-46
references.pmid: 9989456
references.citation: Front Biosci. 2008 Jan 01;13:657-76
references.pmid: 17981578
references.citation: Biochim Biophys Acta. 2003 Mar 10;1610(2):281-90
references.pmid: 12648781
references.citation: J Neural Transm Suppl. 1998;54:259-67
references.pmid: 9850934
references.citation: Lipids. 2004 Apr;39(4):293-309
references.pmid: 15357017
references.citation: Cell Mol Life Sci. 2006 Feb;63(3):255-67
references.pmid: 16378247
references.citation: J Neural Transm (Vienna). 2005 Aug;112(8):1057-71
references.pmid: 15682268
references.citation: Neuropathol Appl Neurobiol. 2007 Oct;33(5):523-32
references.pmid: 17573808
references.citation: Anal Biochem. 2005 Jan 1;336(1):51-9
references.pmid: 15582558
references.citation: Physiol Rev. 2001 Jan;81(1):153-208
references.pmid: 11152757
references.citation: J Biol Chem. 2007 Sep 14;282(37):26832-26844
references.pmid: 17646164
references.citation: J Alzheimers Dis. 2005 Apr;7(2):103-17; discussion 173-80
references.pmid: 15851848
references.citation: Nat Med. 2005 May;11(5):545-50
references.pmid: 15834426
references.citation: Cell. 2010 Feb 19;140(4):579-89
references.pmid: 20178749
references.citation: Neurochem Int. 2007 Jul-Sep;51(2-4):92-104
references.pmid: 17590478
references.citation: Int J Mol Med. 1999 Jun;3(6):597-600
references.pmid: 10341289
references.citation: J Biol Chem. 2005 Dec 23;280(51):41793-804
references.pmid: 16221687
references.citation: J Lipid Res. 1980 Jul;21(5):505-17
references.pmid: 6995544
references.citation: Brain Res Mol Brain Res. 2004 Mar 17;122(1):17-23
references.pmid: 14992812
references.citation: Hum Mol Genet. 1999 Jul;8(7):1263-9
references.pmid: 10369872
references.citation: QJM. 2001 Sep;94(9):485-90
references.pmid: 11528012
references.citation: Anal Biochem. 2008 Jul 15;378(2):138-43
references.pmid: 18457649
references.citation: Eur J Biochem. 2001 Sep;268(18):4850-9
references.pmid: 11559353
references.citation: Leuk Res. 2010 Mar;34(3):344-51
references.pmid: 19646757
references.citation: Proc Natl Acad Sci U S A. 2001 May 8;98(10):5815-20
references.pmid: 11309494
references.citation: Biochim Biophys Acta. 2009 May;1788(5):964-72
references.pmid: 19366591
references.citation: Genes Dev. 2005 Jan 1;19(1):1-49
references.pmid: 15630019
references.citation: Neuroreport. 1999 Jun 3;10(8):1699-705
references.pmid: 10501560
references.citation: Anal Bioanal Chem. 2008 Oct;392(4):673-80
references.pmid: 18690423
references.citation: Neurobiol Dis. 2009 Aug;35(2):251-7
references.pmid: 19464372
references.citation: Pharmacopsychiatry. 2003 Sep;36 Suppl 2:S144-8
references.pmid: 14574629
references.citation: J Lipid Res. 1997 Nov;38(11):2216-23
references.pmid: 9392419
references.citation: Proc Natl Acad Sci U S A. 2001 May 8;98(10):5856-61
references.pmid: 11296263
references.citation: J Lipid Res. 2005 May;46(5):904-12
references.pmid: 15716592
references.citation: Traffic. 2001 May;2(5):303-10
references.pmid: 11350626
references.citation: J Biol Chem. 2008 May 16;283(20):14132-43
references.pmid: 18347024