Puglielli Luigi, Ellis Blake C, Ingano Laura A MacKenzie, Kovacs Dora M
Neurobiology of Disease Laboratory, Genetics and Aging Research Unit/NIND, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
J Mol Neurosci. 2004;24(1):93-6. doi: 10.1385/JMN:24:1:093.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory deficit, cognitive impairment, and personality changes accompanied by specific structural abnormalities in the brain. Deposition of amyloid-beta (Abeta) peptide into senile plaques is a consistent feature of the brains of patients affected by AD. Studies with both animal and cellular models of AD have shown that cholesterol homeostasis and distribution regulate Abeta generation. We have provided genetic, biochemical, and metabolic evidence that implicates intracellular cholesterol distribution, rather than total cholesterol levels, in the regulation of Abeta generation. This minireview focuses on the role of acyl-coenzyme A: cholesterol acyltransferase activity (ACAT) in Abeta generation. In genetically mutant cell lines that overproduce cholesterol but cannot synthesize cholesteryl esters (CEs) because of deficient ACAT activity, Abeta production is almost completely inhibited. Acyl-coenzyme A: cholesterol acyltransferase activity (ACAT) inhibitors, currently being developed for the treatment and prevention of atherosclerosis, reduce CE levels and Abeta generation by up to 50% in cell culture models of AD. Future mechanistic and transgenic animal studies are needed to evaluate the potential use of ACAT inhibitors in the therapeutic treatment or prevention of AD.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征为进行性记忆缺陷、认知障碍和人格改变，并伴有大脑特定的结构异常。β-淀粉样蛋白（Aβ）肽沉积形成老年斑是AD患者大脑的一个一致特征。对AD动物模型和细胞模型的研究表明，胆固醇稳态和分布调节Aβ的生成。我们已经提供了遗传、生化和代谢证据，表明细胞内胆固醇分布而非总胆固醇水平参与了Aβ生成的调节。本综述聚焦于酰基辅酶A：胆固醇酰基转移酶活性（ACAT）在Aβ生成中的作用。在因ACAT活性缺陷而过量产生胆固醇但无法合成胆固醇酯（CE）的基因工程突变细胞系中，Aβ的产生几乎被完全抑制。目前正在开发用于治疗和预防动脉粥样硬化的酰基辅酶A：胆固醇酰基转移酶活性（ACAT）抑制剂，在AD细胞培养模型中可使CE水平和Aβ生成降低多达50%。未来需要进行机制研究和转基因动物研究，以评估ACAT抑制剂在治疗或预防AD方面的潜在用途。
