title: Statins and the squalene synthase inhibitor zaragozic acid stimulate the non-amyloidogenic pathway of amyloid-beta protein precursor processing by suppression of cholesterol synthesis.
abstract: Cholesterol-lowering drugs such as statins influence the proteolytic processing of the amyloid-beta protein precursor (AbetaPP) and are reported to stimulate the activity of alpha-secretase, the major preventive secretase of Alzheimer's disease. Statins can increase the alpha-secretase activity by their cholesterol-lowering properties as well as by impairment of isoprenoids synthesis. In the present study, we elucidate the contribution of these pathways in alpha-secretase activation. We demonstrate that zaragozic acid, a potent inhibitor of squalene synthase which blocks cholesterol synthesis but allows synthesis of isoprenoids, also stimulates alpha-secretase activity. Treatment of human neuroblastoma cells with 50 microM zaragozic acid resulted in a approximately 3 fold increase of alpha-secretase activity and reduced cellular cholesterol by approximately 30%. These effects were comparable to results obtained from cells treated with a low lovastatin concentration (2 microM). Zaragozic acid-stimulated secretion of alpha-secretase-cleaved soluble AbetaPP was dose dependent and saturable. Lovastatin- or zaragozic acid-stimulated increase of alpha-secretase activity was completely abolished by a selective ADAM10 inhibitor. By targeting the alpha-secretase ADAM10 to lipid raft domains via a glycosylphosphatidylinositol anchor, we demonstrate that ADAM10 is unable to cleave AbetaPP in a cholesterol-rich environment. Our results indicate that inhibition of cholesterol biosynthesis by a low lovastatin concentration is sufficient for alpha-secretase activation.
authors.affiliation: Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University, Mainz, Germany. kojro@uni-mainz.de
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Kojro
authors.forename: Petra
authors.initials: P
authors.lastname: Füger
authors.forename: Claudia
authors.initials: C
authors.lastname: Prinzen
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Kanarek
authors.forename: Dorothea
authors.initials: D
authors.lastname: Rat
authors.forename: Kristina
authors.initials: K
authors.lastname: Endres
authors.forename: Falk
authors.initials: F
authors.lastname: Fahrenholz
authors.forename: Rolf
authors.initials: R
authors.lastname: Postina
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis*; D004789:Enzyme Activation / Q000187:drug effects; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013729:Terpenes / Q000494:pharmacology; D014233:Tricarboxylic Acids / Q000494:pharmacology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D000924:Anticholesteremic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D013729:Terpenes; D014233:Tricarboxylic Acids; C075117:squalestatin 1; D002784:Cholesterol; D008148:Lovastatin; D008156:Luciferases; D013186:Farnesyl-Diphosphate Farnesyltransferase; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human