Chen M, Fernandez H L
Neuroscience Research Laboratory, Medical Research Service (151), Bay Pines VA Medical Center, Bay Pines, Florida 33744, USA.
Front Biosci. 1998 Dec 15;3:A66-75. doi: 10.2741/a254.
Abnormality of protease activities and imbalance of intracellular calcium are two most salient aberrant events in Alzheimer's disease (AD). As such, calcium-dependent proteases such as calpain, as a critical link between these two events, must play a key role in the pathogenesis of AD, particularly in the abnormal processing of beta-amyloid precursor protein. Because alpha-secretase in this process appears to be a calcium-dependent protease and its enzymatic characteristics are impressively similar to those of calpain, a challenging possibility arises: Calpain might act as alpha-secretase in vivo. However, as the experimental evidence both for and against this possibility is compelling, the issue currently remains as a theoretical dilemma in which a central question is whether calpain, a cytosolic enzyme, can somehow reach the cell surface. This difficult issue needs to be addressed now. As a first attempt to explore the issue, we propose a working model for the membrane orientation of calpain and suggest several experiments that will critically test this model. The quest to this dilemma will not only impact our understanding of AD, but may also expand the current knowledge about Ca2+ signal transduction pathway. Finally, we discuss several competing models and the potential role of presenilins as "regulators" of alpha-secretase. It is of interest to note that some of our previous theoretical predictions have been experimentally observed.
蛋白酶活性异常和细胞内钙失衡是阿尔茨海默病（AD）中两个最显著的异常事件。因此，钙依赖性蛋白酶如钙蛋白酶，作为这两个事件之间的关键联系，必定在AD的发病机制中起关键作用，尤其是在β淀粉样前体蛋白的异常加工过程中。因为在此过程中α-分泌酶似乎是一种钙依赖性蛋白酶，其酶学特性与钙蛋白酶的酶学特性惊人地相似，所以出现了一种具有挑战性的可能性：钙蛋白酶可能在体内充当α-分泌酶。然而，由于支持和反对这种可能性的实验证据都很有说服力，目前这个问题仍然是一个理论困境，其中一个核心问题是，一种胞质酶钙蛋白酶能否以某种方式到达细胞表面。这个难题现在需要解决。作为探索这个问题的首次尝试，我们提出了一个钙蛋白酶膜取向的工作模型，并提出了几个将严格检验该模型的实验。解决这个困境不仅会影响我们对AD的理解，还可能扩展目前关于Ca2+信号转导途径的知识。最后，我们讨论了几种相互竞争的模型以及早老素作为α-分泌酶“调节因子”的潜在作用。值得注意的是，我们之前的一些理论预测已经得到了实验验证。
