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

被引:389
作者
Puglielli, L
Konopka, G
Pack-Chung, E
Ingano, LAM
Berezovska, O
Hyman, BT
Chang, TY
Tanzi, RE
Kovacs, DM
机构
[1] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Genet & Aging Res Unit, Charlestown, MA 02129 USA
[2] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Alzheimer Res Unit, Charlestown, MA 02129 USA
[3] Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02115 USA
[4] Dartmouth Coll Sch Med, Dept Biochem, Hanover, NH 03755 USA
关键词
D O I
10.1038/ncb1001-905
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The pathogenic event common to all forms of Alzheimer's disease is the abnormal accumulation of the amyloid beta -peptide (A beta). Here we provide strong 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 generation of A beta through the tight control of the equilibrium between free cholesterol and cholesteryl esters. We also show that pharmacological inhibitors of ACAT, developed for the treatment of atherosclerosis, are potent modulators of A beta generation, indicating their potential for use in the treatment of Alzheimer's disease.
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收藏
页码:905 / 912
页数:8
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