title: A specific inhibitor of cholesterol biosynthesis, BM15.766, reduces the expression of beta-secretase and the production of amyloid-beta in vitro.
abstract: We have previously shown that statins reduce the production of amyloid-beta (Abeta) by both isoprenoid- and cholesterol-dependent mechanisms. These pathways contribute to the regulation of the dimerisation of BACE into its physiologically active form. Statins reduce cellular cholesterol levels by 20-40%; therefore, it is possible that the remaining cholesterol within the cell may play a significant role in the production of Abeta. Incubation of cells with the specific cholesterol biosynthesis inhibitor BM15.766 together with 50 micromol/L simvastatin and 400 micromol/L mevalonate reduced cellular cholesterol levels in a dose-dependent manner with increasing BM15.766 concentration (r = -0.9736, p = 0.0264). Furthermore, decreases in cellular cholesterol levels correlated with reductions in total Abeta production (r = 0.9683, p = 0.0317). A total of 2.5 micromol/L BM15.766 inhibited the dimerisation of BACE, whilst the expression of BACE monomer was reduced by 5 micromol/L BM15.766. BM15.766 treatment localised BACE predominantly within the Golgi, and reduced total BACE expression per cell. Similar changes were observed in the expression of the Golgi marker golgin-97, suggesting that reduced BACE expression may arise from a decrease in protein trafficking and an increase in degradation. By targeting cholesterol synthesis using specific cholesterol biosynthesis inhibitors, it is possible to reduce Abeta production without reducing protein isoprenylation.
authors.affiliation: Department of Basic Medical Sciences, St. Georges, University of London, Cranmer Terrace, London, UK. r.parsons@sgul.ac.uk
authors.forename: Richard B
authors.initials: RB
authors.lastname: Parsons
authors.forename: Daryl
authors.initials: D
authors.lastname: Subramaniam
authors.forename: Brian M
authors.initials: BM
authors.lastname: Austen
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000704:Analysis of Variance; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001324:Autoantigens / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002461:Cell Line, Transformed; D002784:Cholesterol / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D000077614:Golgi Matrix Proteins; D006801:Humans; D008798:Mevalonic Acid / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D014162:Transfection / Q000379:methods
chemical_list: D016229:Amyloid beta-Peptides; D000924:Anticholesteremic Agents; D001324:Autoantigens; D000077614:Golgi Matrix Proteins; C450721:Golgi complex autoantigen, 97-kDa; D010879:Piperazines; C047457:BM 15766; D002784:Cholesterol; D053829:Amyloid Precursor Protein Secretases; D008798:Mevalonic Acid