Molecular NeuroscienceThe role of cholesterol in the biosynthesis of β-amyloid.Frears, Emma R.1; Stephens, David J1; Walters, Claire E.1; Davies, Huw2; Austen, Brian M.1,3Author Information 1Neurodegeneration Unit, St George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, UK 2Ciphergen Biosystems Ltd, Prior Road, Camberley, Surrey GU15 1DA, UK 3Corresponding Author: Brian M. Austen ACKNOWLEDGEMENTS: We are grateful to Research into Aging for financial support. Received 17 March 1999; accepted 13 April 1999 NeuroReport: June 3rd, 1999 - Volume 10 - Issue 8 - p 1699-1705 Buy SDC Abstract ADDITION of the β-hydroxy-β-methylglutaryl-CoA (HmG-CoA) reductase inhibitor lovastatin to human HEK cells transfected with the amyloid precursor protein (APP) reduces intracellular cholesterol/protein ratios by 50%, and markedly inhibits β-secretase cleavage of newly-synthesized APP. Exogenous water-solubilized cholesterol at 200 μg/ml concentration increases newly synthesized β-amyloidogenic products four-fold. These intracellular changes are detectable by immunoprecipitation and immunofluorescent labelling. Analyses of the fragments captured from culture medium by an N-terminal anti-β-amyloid antibody on ProteinChip arrays and detected using surface-enhanced laser desorption/ionization (SELDI) mass spectrometry revealed that culture with cholesterol (200 μg/ml) increased secretion of β-amyloid 1–40 by 1.8-fold, and increased secretion of β-amyloid 1–42. Changes in APP processing by cholesterol may mediate the way in which the ApoE4 allele increases risk of developing Alzheimer's disease (AD) in western populations. © 1999 Lippincott Williams & Wilkins, Inc.