title: Knockdown of ACAT-1 reduces amyloidogenic processing of APP.
abstract: Previous studies have shown that acyl-coenzyme A:cholesterol acyl transferase (ACAT), an enzyme that controls cellular equilibrium between free cholesterol and cholesteryl esters, modulates proteolytic processing of APP in cell-based and animal models of Alzheimer's disease. Here we report that ACAT-1 RNAi reduced cellular ACAT-1 protein by approximately 50% and cholesteryl ester levels by 22% while causing a slight increase in the free cholesterol content of ER membranes. This correlated with reduced proteolytic processing of APP and 40% decrease in Abeta secretion. These data show that even a modest decrease in ACAT activity can have robust suppressive effects on Abeta generation.
authors.affiliation: Neurobiology of Disease Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, United States. Henri_Huttunen@hms.harvard.edu
authors.forename: Henri J
authors.initials: HJ
authors.lastname: Huttunen
authors.forename: Christopher
authors.initials: C
authors.lastname: Greco
authors.forename: Dora M
authors.initials: DM
authors.lastname: Kovacs
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D002788:Cholesterol Esters / Q000032:analysis / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000201:enzymology; D006801:Humans; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D002788:Cholesterol Esters; D034741:RNA, Small Interfering; D002785:Sterol O-Acyltransferase; C493492:sterol O-acyltransferase 1