Generation of C-terminally truncated amyloid-β peptides is dependent on γ-secretase activity
Generation of C-terminally truncated amyloid-β peptides is dependent on γ-secretase activity
复制标题
DOI：
10.1046/j.1471-4159.2002.00985.x
复制
发表时间：
2002-08-01
影响因子：
4.7
通讯作者：
Shearman, MS
中科院分区：
文献类型：
--
作者：
Beher, D;Wrigley, JDJ;Shearman, MS
通过β-淀粉样蛋白前体蛋白的加工而异常产生淀粉样蛋白-β肽导致形成特征性细胞外蛋白沉积物，其被认为是阿尔茨海默病的原因。因此，抑制负责淀粉样β肽生成的关键酶β-和γ-分泌酶可能提供干预疾病进展的机会。在人脑和细胞培养系统中，检测到具有各种截短的淀粉样β肽的异质群体，目前尚不清楚它们是如何产生的。我们已经使用了表面增强激光解吸/电离飞行时间质谱（SELDI-TOF MS）和γ-分泌酶的特异性抑制剂的组合，以调查是否所有淀粉样β肽物质的生产需要γ-分泌酶的作用。使用这种方法，我们证明了所有截短的淀粉样β肽的生产，除了那些释放的非淀粉样α-分泌酶或潜在的β-位点β APP裂解酶2的作用依赖于γ-分泌酶的活性。这表明这些肽都不是由单独的酶实体产生的，并且γ-分泌酶的特异性抑制剂应该具有阻断所有淀粉样蛋白生成肽的潜力。此外，在存在γ-分泌酶抑制剂的情况下，观察到α-分泌酶对膜结合β APP C-末端片段C99的切割增加，这表明在其运输过程中C99遇到了α-分泌酶活性所在的隔室。
Aberrant production of amyloid-beta peptides by processing of the beta-amyloid precursor protein leads to the formation of characteristic extracellular protein deposits which are thought to be the cause of Alzheimer's disease. Therefore, inhibiting the key enzymes responsible for amyloid-beta peptide generation, beta- and gamma-secretase may offer an opportunity to intervene with the progression of the disease. In human brain and cell culture systems a heterogeneous population of amyloid-beta peptides with various truncations is detected and at present, it is unclear how they are produced. We have used a combination of surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) and a specific inhibitor of gamma-secretase to investigate whether the production of all amyloid-beta peptide species requires the action of gamma-secretase. Using this approach, we demonstrate that the production of all truncated amyloid-beta peptides except those released by the action of the nonamyloidogenic alpha-secretase enzyme or potentially beta-site betaAPP cleaving enzyme 2 depends on gamma-secretase activity. This indicates that none of these peptides are generated by a separate enzyme entity and a specific inhibitor of the gamma-secretase enzyme should havethe potential to block the generation of all amyloidogenicpeptides. Furthermore in the presence of gamma-secretase inhibitors, the observation of increased cleavage of the membrane-bound betaAPP C-terminal fragment C99 by alpha-secretase suggests that during its trafficking C99 encounters compartments in which alpha-secretase activity resides.