Lipidation of apolipoprotein E influences its isoform-specific interaction with Alzheimer's amyloid β peptides
Lipidation of apolipoprotein E influences its isoform-specific interaction with Alzheimer's amyloid β peptides
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DOI：
10.1042/0264-6021:3480359
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发表时间：
2000-06-01
影响因子：
4.1
通讯作者：
Ghiso, J
中科院分区：
文献类型：
--
作者：
Tokuda, T;Calero, M;Ghiso, J
载脂蛋白E（apoE）β 4等位基因的遗传是散发性和家族性阿尔茨海默病（AD）的主要危险因素。ApoE同种型在体外和体内都直接结合阿尔茨海默氏淀粉样蛋白β（A β）肽。最近的研究表明，apoE与脂质的结合可能会调节其与A β的相互作用。我们研究了结合的脂质相关和脱脂apoE 3和apoE 4亚型A β利用固相结合试验，并估计各种apoE和A β物种的相互作用的解离常数。使用来自稳定转染的RAW 264和人胚肾293细胞的天然apoE同种型，apoE 3对A β 1-40和A β 1-42的亲和力大于apoE 4。apoE的去脂使其对A β肽的亲和力降低了5-10倍，并消除了亚型特异性。相反，将由杆状病毒感染的Sf 9细胞产生的apoE亚型掺入重组的人高密度脂蛋白脂质颗粒中，恢复了A β肽的亲和力值，并导致apoE 3的优先结合。数据表明，天然脂质相关的apoE 3以比脂质相关的apoE 4高2-3倍的亲和力结合A β肽。由于同种型的结合效率与发展迟发性AD的风险呈负相关，因此结果表明apoE 3可能参与A β从中枢神经系统的清除或路由，作为疾病病理学的基础机制之一。
The inheritance of the apolipoprotein E (apoE) epsilon 4 allele is a prevailing risk factor for sporadic and familial Alzheimer's disease (AD). ApoE isoforms bind directly to Alzheimer's amyloid beta (A beta) peptides both in vitro and in vivo. Recent studies suggest that association of apoE with lipids may modulate its interaction with A beta. We examined the binding of lipid-associated and delipidated apoE3 and apoE4 isoforms to A beta utilizing a solid-phase binding assay and estimated the dissociation constants for the interaction of various apoE and A beta species. Using native apoE isoforms from stably transfected RAW 264 and human embryonic kidney 293 cells, apoE3 had greater affinity than apoE4 for both A beta 1-40 and A beta 1-42. Delipidation of apoE decreased its affinity for A beta peptides by 5-10-fold and abolished the isoform-specificity. Conversely, incorporation of apoE iso-forms produced by baculovirus-infected Sf9 cells into reconstituted human high-density-lipoprotein lipoparticles restored the affinity values for A beta peptides and resulted in preferential binding of apoE3. The data demonstrate that native lipid-associated apoE3 binds to A beta peptides with 2-3-fold higher affinity than lipid-associated apoE4. Since the isoforms' binding efficiency correlate inversely with the risk of developing late-onset AD, the results suggest a possible involvement of apoE3 in the clearance or routing out of A beta from the central nervous system as one of the mechanisms underlying the pathology of the disease.