Yamauchi K, Tozuka M, Nakabayashi T, Sugano M, Hidaka H, Kondo Y, Katsuyama T
Central Clinical Laboratories, Shinshu University Hospital, Asahi, Matsumoto, Japan.
J Neurosci Res. 1999 Oct 15;58(2):301-7.
Apolipoprotein E (apoE) is believed to be closely involved in the pathogenesis of Alzheimer's disease (AD) because of its ability to bind to beta-amyloid (Abeta), the primary component of senile plaques. The presence of cystein residues in apoE2 and apoE3 allows these isoforms to form disulfide-linked complexes, such as apo(E-AII) complex and apo(AII-E-AII) complex. A 50-kDa complex [which corresponded to apo(E-AII)-Abeta, because it reacted with any of the three antibodies, anti-apoE, anti-apoAII, or anti-Abeta] was detected by immunoblot analysis in native cerebrospinal fluid (CSF) obtained from nondementia patients with the apoE phenotype E3/E3. However, a band considered to represent apoE-Abeta was not observed. The dissociation constant (Kd) values obtained for the specific binding of recombinant apoE2, apoE3, and apoE4 to Abeta(1-42) were 48.1 +/- 2.2 nM, 63.7 +/- 2.1 nM, and 75.9 +/- 1.8 nM, respectively. In contrast, the binding affinity of the partially purified apo(E3-AII) complex to Abeta(1-42) was very high, the Kd being 5.5 +/- 0.5 nM. No basic difference was observed between lipidated and nonlipidated apoE in terms of the characteristics of the binding of apoE isoforms to Abeta(1-42); however, lipidation reduced the binding capacity of each isoform in a dose-dependent manner. These findings seem consistent with the generally accepted idea that apoE4 is a risk factor for AD, insofar as only apoE4 is unable to form a complex with apoAII owing to its lack of a cystein residue. In addition, it is possible that apoE3 monomer (and possibly apoE2 monomer), like apoE4 but unlike apo(E-AII) complex, can act as a risk factor in the pathogenesis of AD.
载脂蛋白E（apoE）被认为与阿尔茨海默病（AD）的发病机制密切相关，因为它能够与老年斑的主要成分β-淀粉样蛋白（Aβ）结合。apoE2和apoE3中半胱氨酸残基的存在使这些异构体能够形成二硫键连接的复合物，如apo（E-AII）复合物和apo（AII-E-AII）复合物。通过免疫印迹分析，在从具有apoE表型E3/E3的非痴呆患者获得的天然脑脊液（CSF）中检测到一种50 kDa的复合物[其对应于apo（E-AII）-Aβ，因为它与三种抗体（抗apoE、抗apoAII或抗Aβ）中的任何一种发生反应]。然而，未观察到被认为代表apoE-Aβ的条带。重组apoE2、apoE3和apoE4与Aβ（1-42）特异性结合的解离常数（Kd）值分别为48.1±2.2 nM、63.7±2.1 nM和75.9±1.8 nM。相比之下，部分纯化的apo（E3-AII）复合物与Aβ（1-42）的结合亲和力非常高，Kd为5.5±0.5 nM。就apoE异构体与Aβ（1-42）结合的特性而言，在脂化和非脂化的apoE之间未观察到基本差异；然而，脂化以剂量依赖的方式降低了每种异构体的结合能力。这些发现似乎与普遍接受的观点一致，即apoE4是AD的危险因素，因为只有apoE4由于缺乏半胱氨酸残基而无法与apoAII形成复合物。此外，apoE3单体（可能还有apoE2单体）与apoE4一样，但与apo（E-AII）复合物不同，有可能在AD的发病机制中作为危险因素起作用。
