Dominguez D I, De Strooper B, Annaert W
Flanders Interuniversitary Institute for Biotechnology and K.U. Leuven, Neuronal Cell Biology and Gene Transfer Laboratory, Center for Human Genetics, Gasthuisberg, B-3000 Leuven, Belgium.
Amyloid. 2001 Jun;8(2):124-42. doi: 10.3109/13506120109007356.
The extracellular deposition of short amyloid peptides in the brain of patients is thought to be a central event in the pathogenesis of Alzheimer's Disease. The generation of the amyloid peptide occurs via a regulated cascade of cleavage events in its precursor protein, A beta PP. At least three enzymes are responsible for A beta PP proteolysis and have been tentatively named alpha-, beta- and gamma-secretases. The recent identification of several of these secretases is a major leap in the understanding how these secretases regulate amyloid peptide formation. Members of the ADAM family of metalloproteases are involved in the non-amyloidogenic alpha-secretase pathway. The amyloidogenic counterpart pathway is initiated by the recently cloned novel aspartate protease named BACE. The available data are conclusive and crown BACE as the long-sought beta-secretase. This enzyme is a prime candidate drug target for the development of therapy aiming to lower the amyloid burden in the disease. Finally, the gamma-secretases are intimately linked to the function of the presenilins. These multi-transmembrane domain proteins remain intriguing study objects. The hypothesis that the presenilins constitute a complete novel type of protease family, and are cleaving A beta PP within the transmembrane region, remains an issue of debate. Several questions remain unanswered and direct proof that they exert catalytic activity is still lacking. The subcellular localization of presenilins in neurons, their integration in functional multiprotein complexes and the recent identification of additional modulators of gamma-secretase, like nicastrin, indicate already that several players are involved. Nevertheless, the rapidly increasing knowledge in this area is already paving the road towards selective inhibitors of this secretase as well. It is hoped that such drugs, possibly in concert with the experimental vaccination therapies that are currently tested, will lead to a cure of this inexorable disease.
短淀粉样肽在阿尔茨海默病患者大脑中的细胞外沉积被认为是该疾病发病机制中的核心事件。淀粉样肽的产生是通过其前体蛋白β淀粉样前体蛋白（AβPP）中一系列受调控的切割事件实现的。至少有三种酶负责AβPP的蛋白水解，并被暂定为α-、β-和γ-分泌酶。最近对其中几种分泌酶的鉴定是在理解这些分泌酶如何调节淀粉样肽形成方面的一个重大飞跃。金属蛋白酶ADAM家族的成员参与了非淀粉样生成的α-分泌酶途径。淀粉样生成的对应途径由最近克隆的新型天冬氨酸蛋白酶BACE启动。现有数据确凿，确认BACE就是长期寻找的β-分泌酶。这种酶是开发旨在降低疾病中淀粉样蛋白负荷的治疗方法的主要候选药物靶点。最后，γ-分泌酶与早老素的功能密切相关。这些多跨膜结构域蛋白仍然是引人入胜的研究对象。早老素构成一种全新类型的蛋白酶家族并在跨膜区域内切割AβPP的假说仍然存在争议。几个问题仍未得到解答，并且仍然缺乏它们发挥催化活性的直接证据。早老素在神经元中的亚细胞定位、它们在功能性多蛋白复合物中的整合以及最近对γ-分泌酶其他调节剂（如尼卡斯特林）的鉴定已经表明有多个参与者。然而，该领域迅速增长的知识也已经为这种分泌酶的选择性抑制剂铺平了道路。人们希望这样的药物，可能与目前正在测试的实验性疫苗疗法协同作用，将能够治愈这种无法阻挡的疾病。
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