Acyl-coenzyme A : cholesterol acyltransferase modulates the generation of the amyloid beta-peptide

The pathogenic event common to all forms of Alzheimer's disease is the abno rmal accumulation of the amyloid beta -peptide (A beta). Here we provide st rong evidence that intracellular cholesterol compartmentation modulates the generation of A beta. Using genetic, biochemical and metabolic approaches, we found that cholesteryl-ester levels are directly correlated with A beta production. Acyl-coenzyme A:cholesterol acyltransferase (ACAT), the enzyme that catalyses the formation of cholesteryl esters, modulates the generati on of A beta through the tight control of the equilibrium between free chol esterol and cholesteryl esters. We also show that pharmacological inhibitor s of ACAT, developed for the treatment of atherosclerosis, are potent modul ators of A beta generation, indicating their potential for use in the treat ment of Alzheimer's disease.