BINDING OF HUMAN APOLIPOPROTEIN-E TO SYNTHETIC AMYLOID-BETA PEPTIDE - ISOFORM-SPECIFIC EFFECTS AND IMPLICATIONS FOR LATE-ONSET ALZHEIMER-DISEASE
BINDING OF HUMAN APOLIPOPROTEIN-E TO SYNTHETIC AMYLOID-BETA PEPTIDE - ISOFORM-SPECIFIC EFFECTS AND IMPLICATIONS FOR LATE-ONSET ALZHEIMER-DISEASE
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DOI：
10.1073/pnas.90.17.8098
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发表时间：
1993-09-01
影响因子：
11.1
通讯作者：
ROSES, AD
中科院分区：
文献类型：
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作者：
STRITTMATTER, WJ;WEISGRABER, KH;ROSES, AD
载脂蛋白E（apoE）是一种在脂蛋白代谢中起核心作用的血浆载脂蛋白，定位于老年斑、嗜酸性血管病和阿尔茨海默病的神经系统缠结中。迟发性家族性和散发性阿尔茨海默病患者的三种常见apoE等位基因之一ε 4的频率增加，表明apoE 4与疾病易感性增加相关。为了跟进这一建议，我们比较了合成的淀粉样β（β/A4）肽与纯化的apoE 4和apoE 3（最常见的同种型）的结合。这两种亚型结合合成β/A4肽，斑块和血管病的主要成分，形成复合物，抵抗在SDS中沸腾分解。氧介导的复合物的形成是有牵连的，因为结合在含氧缓冲液中增加，在氮气净化的缓冲液中减少，并通过用二硫苏糖醇或2-巯基乙醇还原来防止。β/A4肽的结合在10（-4）M肽下是饱和的，并且需要残基12-28。对apoE片段的检查揭示了残基244-272对于复合物的形成是关键的。氧化的apoE 4和apoE 3都能结合β/A4肽;然而，与apoE 4的结合在几分钟内就能观察到，而与apoE 3的结合需要几个小时。此外，apoE 4在pH < 6.6时不结合β/A4肽，而apoE 3在pH 7.6至4.6时结合β/A4肽。这些结果共同表明两种同种型在与β/A4肽复合方面的差异。氧化apoE与β/A4肽的结合可能决定apoE或β/A4肽的螯合或靶向，apoE结合或氧化的亚型特异性差异可能参与阿尔茨海默病细胞内和细胞外病变的发病机制。
Apolipoprotein E (apoE), a plasma apolipoprotein that plays a central role in lipoprotein metabolism, is localized in the senile plaques, congophilic angiopathy, and neurofibrillary tangles of Alzheimer disease. Late-onset familial and sporadic Alzheimer disease patients have an increased frequency of one of the three common apoE alleles, epsilon4, suggesting apoE4 is associated with increased susceptibility to disease. To follow up on this suggestion, we compared the binding of synthetic amyloid beta (beta/A4) peptide to purified apoE4 and apoE3, the most common isoform. Both isoforms bound synthetic beta/A4 peptide, the primary constituent of the plaque and angiopathy, forming a complex that resisted dissociation by boiling in SDS. Oxygen-mediated complex formation was implicated because binding was increased in oxygenated buffer, reduced in nitrogen-purged buffer, and prevented by reduction with dithiothreitol or 2-mercaptoethanol. Binding of beta/A4 peptide was saturable at 10(-4) M peptide and required residues 12-28. Examination of apoE fragments revealed that residues 244-272 are critical for complex formation. Both oxidized apoE4 and apoE3 bound beta/A4 peptide; however, binding to apoE4 was observed in minutes, whereas binding to apoE3 required hours. In addition, apoE4 did not bind beta/A4 peptide at pH < 6.6, whereas apoE3 bound beta/A4 peptide from pH 7.6 to 4.6. Together these results indicate differences in the two isoforms in complexing with the beta/A4 peptide. Binding of beta/A4 peptide by oxidized apoE may determine the sequestration or targeting of either apoE or beta/A4 peptide, and isoform-specific differences in apoE binding or oxidation may be involved in the pathogenesis of the intra- and extracellular lesions of Alzheimer disease.