A specific inhibitor of cholesterol biosynthesis, BM15.766, reduces the expression of beta-secretase and the production of amyloid-beta in vitro.
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.
Parsons
Richard B
RB
Department of Basic Medical Sciences, St. Georges, University of London, Cranmer Terrace, London, UK. r.parsons@sgul.ac.uk
Subramaniam
Daryl
D
Austen
Brian M
BM
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
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