The role of cholesterol in the biosynthesis of beta-amyloid.
Addition of the beta-hydroxy-beta-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 beta-secretase cleavage of newly-synthesized APP. Exogenous water-solubilized cholesterol at 200 microg/ml concentration increases newly synthesized beta-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-beta-amyloid antibody on ProteinChip arrays and detected using surface-enhanced laser desorption/ionization (SELDI) mass spectrometry revealed that culture with cholesterol (200 microg/ml) increased secretion of beta-amyloid 1-40 by 1.8-fold, and increased secretion of beta-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.
Frears
E R
ER
Neurodegeneration Unit, St George's Hospital Medical School, London, UK.
Stephens
D J
DJ
Walters
C E
CE
Davies
H
H
Austen
B M
BM
D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D002784:Cholesterol / Q000494:pharmacology / Q000502:physiology*; D002851:Chromatography, High Pressure Liquid; D016895:Culture Media, Serum-Free; D005455:Fluorescent Antibody Technique; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology; D013058:Mass Spectrometry; D010446:Peptide Fragments / Q000096:biosynthesis; D011233:Precipitin Tests; D014162:Transfection
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016895:Culture Media, Serum-Free; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010446:Peptide Fragments; D002784:Cholesterol; D008148:Lovastatin