Protection against amyloid beta-peptide (1-42)-induced loss of phospholipid asymmetry in synaptosomal membranes by tricyclodecan-9-xanthogenate (D609) and ferulic acid ethyl ester: Implications for Alzheimer's disease
Protection against amyloid beta-peptide (1-42)-induced loss of phospholipid asymmetry in synaptosomal membranes by tricyclodecan-9-xanthogenate (D609) and ferulic acid ethyl ester: Implications for Alzheimer's disease
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DOI：
10.1016/j.bbadis.2004.12.002
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发表时间：
2005-06-30
影响因子：
6.2
通讯作者：
Butterfield, DA
中科院分区：
文献类型：
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作者：
Abdul, HM;Butterfield, DA
脑中淀粉样蛋白-β（1-42）[A β（1-42）]沉积是阿尔茨海默病（AD）的标志，并已显示诱导细胞凋亡和破坏细胞离子稳态。A β（1-42）诱导膜脂质过氧化，4-羟基壬烯醛（HNE）和2-丙烯醛（丙烯醛）是脂质过氧化的两种反应产物，它们通过共价相互作用在结构上修饰蛋白质并抑制酶功能。磷脂酰丝氨酸（PS）是一种氨基磷脂，在未受刺激的细胞中被隔离在质膜的内小叶中。突触体凋亡的早期信号是磷脂不对称性的丧失和膜外小叶中磷脂酰丝氨酸的出现。ATP需要酶，翻转酶，维持PS的磷脂不对称性。在此，我们研究了A（1-42）对跨膜酶氨基磷脂转位酶（或翻转酶）的失活作用。翻转酶活性取决于一个关键的半胱氨酸残基，这是A β（1-42）诱导的脂质过氧化产物HNE或丙烯醛共价修饰的假定位点。本研究旨在探讨三环癸烷-9-黄原酸酯（D 609）和阿魏酸乙酯（FAEE）对A（1-42）诱导的突触体膜磷脂不对称性的保护作用。用D 609和FAEE预处理突触体可显著保护A β（1-42）诱导的突触体膜磷脂不对称性丧失。我们的结果表明，D 609和FAEE对A（1-42）诱导的细胞凋亡具有保护作用。胞内Ca ~（2+）的增加可能不是翻转酶活性丧失的唯一原因。相反，其他机制，可以调节翻转酶的功能可能是重要的磷脂不对称的调制。本研究的结果进行了讨论与AD脑神经元丢失的相关性。(c)2004 Elsevier B. V.保留所有权利。
Amyloid-beta (1-42) [A beta (1-42)] deposition in the brain is a hallmark of Alzheimer's disease (AD) and has been shown to induce apoptosis and disrupt cellular ion homeostasis. A beta (1-42) induces membrane lipid peroxidation, and 4-hydroxynonenal (HNE) and 2-propenal (acrolein) are the two reactive products of lipid peroxidation, which structurally modify proteins by covalent interaction and inhibit enzyme function. Phosphatidylserine (PS), an aminophospholipid, is sequestered in the inner leaflet of the plasma membrane in nonstimulated cells. An early signal of synaptosomal apoptosis is the loss of phospholipid asymmetry and the appearance of phosphatidylserine in the outer leaflet of the membrane. The ATP-requiring enzyme, flippase, maintains phospholipid asymmetry of PS. Here, we have investigated the inactivation of the transmembrane enzyme aminophospholipid-translocase (or flippase) by A (1-42). Flippase activity depends on a critical cysteine residue, a putative site of covalent modification by the A beta (1-42)-induced lipid peroxidation products, HNE or acrolein. The present study is aimed to investigate the protective effects of tricyclodecan-9-xanthogenate (D609) and ferulic acid ethyl ester (FAEE) on A (1-42) induced modulation in phospholipid asymmetry in the synaptosomal membranes. Pretreatment of synaptosomes with D609 and FAEE significantly protected A beta (1-42)-induced loss of phospholipid asymmetry in synaptosomal membranes. Our results suggest that D609 and FAEE exert protective effects against A (1-42) induced apoptosis. The increase in intracellular Ca2+ might not be the sole cause for the loss of flippase activity. Rather, other mechanisms that could modulate the function of flippase might be important in the modulation of phospholipid asymmetry. The results of this study are discussed with relevance to neuronal loss in the AD brain. (c) 2004 Elsevier B.V. All rights reserved.