Acyl-coenzyme A:cholesterol acyltransferase modulates the generation of the amyloid β-peptide
Acyl-coenzyme A:cholesterol acyltransferase modulates the generation of the amyloid β-peptide
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DOI：
10.1038/ncb1001-905
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发表时间：
2001-10-01
影响因子：
21.3
通讯作者：
Kovacs, DM
中科院分区：
文献类型：
--
作者：
Puglielli, L;Konopka, G;Kovacs, DM
所有形式的阿尔茨海默病共同的致病事件是淀粉样β肽（A β）的异常积累。在这里，我们提供了强有力的证据表明细胞内胆固醇区室化调节A β的产生。使用遗传，生物化学和代谢方法，我们发现胆固醇酯水平与A β的产生直接相关。酰基辅酶A：胆固醇酰基转移酶（ACAT），催化胆固醇酯形成的酶，通过严格控制游离胆固醇和胆固醇酯之间的平衡来调节A β的产生。我们还表明，ACAT的药理学抑制剂，开发用于治疗动脉粥样硬化，是有效的调节剂的A β生成，表明其潜在的用于治疗阿尔茨海默病。
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.