Inhibition of acyl-coenzyme A: cholesterol acyl transferase modulates amyloid precursor protein trafficking in the early secretory pathway
Inhibition of acyl-coenzyme A: cholesterol acyl transferase modulates amyloid precursor protein trafficking in the early secretory pathway
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DOI：
10.1096/fj.09-134999
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发表时间：
2009-11-01
期刊：
影响因子：
4.8
通讯作者：
Kovacs, Dora M.
中科院分区：
文献类型：
--
作者：
Huttunen, Henri J.;Peach, Camilla;Kovacs, Dora M.
淀粉样β-肽（A β）在阿尔茨海默病（AD）的发病机制中具有核心作用。细胞胆固醇稳态调节淀粉样前体蛋白（APP）的内蛋白水解生成A β。先前的研究已经确定酰基辅酶A：胆固醇酰基转移酶（ACAT），一种调节亚细胞胆固醇分布的酶，作为AD的潜在治疗靶点。ACAT活性的抑制通过一种未知的机制减少了AD细胞和动物模型中A β的产生。在这里，我们表明，ACAT抑制保留了一部分APP分子在早期分泌途径，限制了APP分泌酶介导的蛋白水解加工的可用性。ACAT抑制剂延迟了未成熟APP分子从内质网（ER）的运输，如代谢标记和活细胞成像所示。这导致APP的部分ER保留和增强ER相关的蛋白酶体降解APP，而不激活未折叠的蛋白反应途径。在接受ACAT抑制剂治疗的小鼠脑中，成熟APP与未成熟APP的比例降低，并且与个体动物脑APP-C99和脑脊液A β水平降低密切相关。我们的研究结果确定了一种新的ACAT依赖性机制，该机制调节APP的分泌运输，可能有助于减少体内A β的产生。胡图嫩湖J.，Peach，C.，巴塔查里亚河，巴伦角，Pettingell，W.，Hutter-Paier，B.，温迪施，M.，别列佐夫斯卡岛科瓦奇山M.抑制酰基辅酶A：胆固醇酰基转移酶调节淀粉样前体蛋白在早期分泌途径中的运输。FASEB J.23，3819-3828（2009）. www.fasebj.org
Amyloid beta-peptide (A beta) has a central role in the pathogenesis of Alzheimer's disease (AD). Cellular cholesterol homeostasis regulates endoproteolytic generation of A beta from the amyloid precursor protein (APP). Previous studies have identified acylcoenzyme A: cholesterol acyltransferase (ACAT), an enzyme that regulates subcellular cholesterol distribution, as a potential therapeutic target for AD. Inhibition of ACAT activity decreases A beta generation in cell-and animal-based models of AD through an unknown mechanism. Here we show that ACAT inhibition retains a fraction of APP molecules in the early secretory pathway, limiting the availability of APP for secretase-mediated proteolytic processing. ACAT inhibitors delayed the trafficking of immature APP molecules from the endoplasmic reticulum (ER) as shown by metabolic labeling and live-cell imaging. This resulted in partial ER retention of APP and enhanced ER-associated degradation of APP by the proteasome, without activation of the unfolded protein response pathway. The ratio of mature APP to immature APP was reduced in brains of mice treated with ACAT inhibitors, and strongly correlated with reduced brain APP-C99 and cerebrospinal fluid A beta levels in individual animals. Our results identify a novel ACAT-dependent mechanism that regulates secretory trafficking of APP, likely contributing to decreased A beta generation in vivo.-Huttunen, H. J., Peach, C., Bhattacharyya, R., Barren, C., Pettingell, W., Hutter-Paier, B., Windisch, M., Berezovska, O., Kovacs, D. M. Inhibition of acyl-coenzyme A: cholesterol acyl transferase modulates amyloid precursor protein trafficking in the early secretory pathway. FASEB J. 23, 3819-3828 (2009). www.fasebj.org