Lansbury P T
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, USA.
Arzneimittelforschung. 1995 Mar;45(3A):432-4.
Amyloid formation in the brain is diagnostic of Alzheimer's disease (AD). However, it is not known whether amyloidogenesis precedes and possibly causes cell death or is a byproduct of cell lysis. In any event, it is critical to understand the time course of amyloid formation. The mechanism of amyloidogenesis has been studied in a simple in vitro model system which can be modified to dissect the factors which may be important in vivo. The studies described herein deal with two factors which are known to be important in vivo; the length of the beta protein C-terminus and the endogenous molecule apolipoprotein E (apoE). It could be shown that the C-terminal sequence of the beta-amyloid protein is a critical determinant of the rate of amyloid formation. This discovery led us to propose that the production of the C-terminally extended variants may be a pathogenic event in familial AD. The APOE allele has been shown to be a susceptibility factor for non-familial AD. The apoE variants have been shown to be amyloid nucleation inhibitors. These proteins probably serve as endogenous amyloid suppressors.
大脑中淀粉样蛋白的形成是阿尔茨海默病（AD）的诊断依据。然而，尚不清楚淀粉样蛋白生成是先于细胞死亡并可能导致细胞死亡，还是细胞裂解的副产物。无论如何，了解淀粉样蛋白形成的时间进程至关重要。淀粉样蛋白生成机制已在一个简单的体外模型系统中进行了研究，该系统可进行修改以剖析在体内可能重要的因素。本文所述的研究涉及两个已知在体内很重要的因素；β蛋白C末端的长度和内源性分子载脂蛋白E（apoE）。可以证明，β淀粉样蛋白的C末端序列是淀粉样蛋白形成速率的关键决定因素。这一发现使我们提出，C末端延伸变体的产生可能是家族性AD中的致病事件。APOE等位基因已被证明是非家族性AD的易感因素。apoE变体已被证明是淀粉样蛋白成核抑制剂。这些蛋白质可能作为内源性淀粉样蛋白抑制剂。
