Hooper N M, Turner A J
Proteolysis Research Group, School of Biochemistry and Molecular Biology, University of Leeds, UK.
Curr Med Chem. 2002 Jun;9(11):1107-19. doi: 10.2174/0929867023370121.
In the nonamyloidogenic processing pathway the Alzheimer s amyloid precursor protein (APP) is proteolytically cleaved by alpha-secretase. As this cleavage occurs at the Lys16-Leu17 bond within the amyloid beta domain, it prevents deposition of intact amyloidogenic peptide. In addition, the large ectodomain (sAPP(alpha)) released by the action of alpha-secretase has several neuroprotective properties. Studies with a range of hydroxamic acid-based compounds, such as batimastat, indicate that alpha-secretase is a zinc metalloproteinase, and members of the adamalysin family of proteins, TACE, ADAM10 and ADAM9, all fulfil some of the criteria required of alpha-secretase. APP is constitutively cleaved by alpha-secretase in most cell lines. However, on stimulation with muscarinic agonists or activators of protein kinase C, such as phorbol esters, the alpha-secretase cleavage of APP is up-regulated. The constitutive alpha-secretase activity is primarily at the cell surface, while the regulated activity is predominantly located within the Golgi. The beneficial action of cholinesterase inhibitors may in part be due to activation of muscarinic receptors, resulting in an up-regulation of alpha-secretase. Other agents can also increase the nonamyloidogenic cleavage of APP including estrogen, testosterone, various neurotransmitters and growth factors. As the alpha-secretase cleavage of APP both precludes the deposition of the amyloid beta peptide and releases the neuroprotective sAPP(alpha), pharmacological up-regulation of alpha-secretase may provide alternative therapeutic approaches for Alzheimer s disease.
在非淀粉样蛋白生成加工途径中，阿尔茨海默病淀粉样前体蛋白（APP）被α-分泌酶进行蛋白水解切割。由于这种切割发生在淀粉样β结构域内的Lys16-Leu17键处，所以可防止完整的淀粉样生成肽沉积。此外，α-分泌酶作用释放的大片段胞外结构域（sAPPα）具有多种神经保护特性。对一系列基于异羟肟酸的化合物（如batimastat）的研究表明，α-分泌酶是一种锌金属蛋白酶，而解整合素金属蛋白酶家族的成员TACE、ADAM10和ADAM9均满足α-分泌酶所需的部分标准。在大多数细胞系中，APP可被α-分泌酶组成性切割。然而，在用毒蕈碱激动剂或蛋白激酶C激活剂（如佛波酯）刺激时，APP的α-分泌酶切割会上调。组成性α-分泌酶活性主要位于细胞表面，而调节性活性主要位于高尔基体。胆碱酯酶抑制剂的有益作用可能部分归因于毒蕈碱受体的激活，从而导致α-分泌酶上调。其他药物也可增加APP的非淀粉样蛋白生成切割，包括雌激素、睾酮、各种神经递质和生长因子。由于APP的α-分泌酶切割既能防止淀粉样β肽沉积，又能释放神经保护性sAPPα，α-分泌酶的药理学上调可能为阿尔茨海默病提供替代治疗方法。
