Chong Y H, Suh Y H
Department of Microbiology, College of Medicine, Ewha Womans University, Seoul, Korea.
Life Sci. 1996;59(7):545-57. doi: 10.1016/0024-3205(96)00335-9.
Recent studies implicate that excessive amyloidogenic pathway of amyloid precursor protein (APP) processing may be the final common pathway involved in the pathogensis of AD. In attempts to identify the proteases or factors leading to excessive amyloid deposition, we evaluated the potential role of acethylcholinesterase (AChE) and its associated protease for amyloidogenic processing of APP in vitro. Prolonged incubation of a recombinant APP770 with AChE produced several amyloidogenic fragments accumulating a relatively stable a 18 kDa A beta (amyloid beta-protein) bearing carboxy terminal peptide, which was further degraded by an increased concentration of AChE. Protease inhibitory profiles confirmed the trypsin-like serine protease activity present in AChE preparation. This observed APP processing was significantly enhanced by Ca2+, Mg2+, or Mn2+ at 1 mM concentration and modulated in concentration dependent manners by metal ions such as Ca2+, Zn2+, Fe2+/Fe3+, Al3+, or a tacrine, a centrally active cholinesterase inhibitor. Our data imply that AChE and its associated protease may be involved in the generation a 18 kDa amyloidogenic peptide under certain physiological condition in vivo and that the gradual changes in their proteolytic activities or locations and the locally disturbed metal homeostasis could be factors associated with abnormal accumulation of APP, eventually leading to amyloid deposition in AD brain. In addition, zinc or tacrine treatment of AD patients with high dosage or in the long term may have effects on the process of amyloidogensis.
最近的研究表明，淀粉样前体蛋白（APP）加工的过度淀粉样生成途径可能是参与阿尔茨海默病（AD）发病机制的最终共同途径。为了确定导致淀粉样蛋白过度沉积的蛋白酶或因素，我们在体外评估了乙酰胆碱酯酶（AChE）及其相关蛋白酶对APP淀粉样生成加工的潜在作用。重组APP770与AChE长时间孵育产生了几个淀粉样生成片段，积累了一种相对稳定的含有羧基末端肽的18 kDa Aβ（淀粉样β蛋白），其会被浓度增加的AChE进一步降解。蛋白酶抑制谱证实了AChE制剂中存在类胰蛋白酶丝氨酸蛋白酶活性。在1 mM浓度下，Ca2+、Mg2+或Mn2+显著增强了观察到的APP加工过程，而Ca2+、Zn2+、Fe2+/Fe3+、Al3+或他克林（一种中枢活性胆碱酯酶抑制剂）等金属离子则以浓度依赖的方式对其进行调节。我们的数据表明，AChE及其相关蛋白酶可能在体内某些生理条件下参与18 kDa淀粉样生成肽的产生，并且它们蛋白水解活性或位置的逐渐变化以及局部紊乱的金属稳态可能是与APP异常积累相关的因素，最终导致AD脑中的淀粉样蛋白沉积。此外，高剂量或长期用锌或他克林治疗AD患者可能会对淀粉样生成过程产生影响。
