Knockdown of ACAT-1 reduces amyloidogenic processing of APP

Neurobiology of Disease Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, United States.
FEBS Letters (Impact Factor: 3.17). 05/2007; 581(8):1688-92. DOI: 10.1016/j.febslet.2007.03.056
Source: PubMed


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.

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Available from: Dora M Kovacs
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    • "Some other enzymes may also be involved with Aâ, such as acyl-coenzyme A cholesterol acyltransferase (ACAT-1), an enzyme that controls cellular equilibrium between free cholesterol and cholesteryl ester and modulates the proteolytic processing of APP in cell-based and animal models of AD.58,59 ACAT-1 RNAi, through a single transfection of ACAT-1 siRNA oligonucleotides, reduces cellular ACAT-1 protein by ~50%, cholesteryl ester levels by 22%, and causes a slight increase in the free cholesterol content of ER membranes, which correlates with reduced proteolytic processing of APP and a 40% decrease in Aâ secretion.60 In addition, endogenous ferritin knockdown by RNAi can decrease iron in mammal cell cultures and promote the formation of well-ordered aggregates of Aâ while decreasing its toxicity.61 "
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