Alternative pathways for production of beta-amyloid peptides of Alzheimer's disease.
Alternative pathways for production of beta-amyloid peptides of Alzheimer's disease.
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生产阿尔茨海默氏病的β-淀粉样蛋白肽的替代途径。
DOI：
10.1515/bc.2008.124
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发表时间：
2008-08
影响因子：
3.7
通讯作者：
Hook G
中科院分区：
文献类型：
--
作者：
Hook V;Schechter I;Demuth HU;Hook G
这篇重点文章描述了在国际蛋白质分解学会第5届大会上发表的三篇阿尔茨海默病(AD)演讲，阐述了产生神经毒性β-淀粉样蛋白(Aβ)多肽的酶机制。一个小组描述了在大多数AD患者中发现的用于切割APP中野生型β分泌酶位点的BACE1β分泌酶的动力学性质很差。他们发现组织蛋白酶D显示出类似于BACE1的特异性，在人脑中的含量是BACE1的280倍，胃抑素A可以抑制脑提取物和组织蛋白酶D对β分泌酶部位多肽的切割，但不能被BCE1切割。然而，由于BCE1和组织蛋白酶D对野生型β分泌酶部位的活性较差，他们建议继续寻找更多的β分泌酶候选者(S)。第二组报道，组织蛋白酶B是这样一种替代的β分泌酶候选基因，对切割野生型β分泌酶具有很好的动力学效率和特异性。值得注意的是，他们证明了组织蛋白酶B的抑制剂改善了记忆功能，减少了淀粉样斑块的神经病理，并降低了表达含有野生型β-分泌酶位点的APP的AD动物模型的脑A-β(40/42)和β-分泌酶活性。第三组讨论了AD大脑中存在的Aβ的异天冬氨酸和焦谷氨酸(PGlu)翻译后修饰，证据表明组织蛋白酶B，而不是BCE1，有效地切割了含有异天冬氨酸的野生型β分泌酶位点。他们还发现，谷氨酰胺环化酶将N-末端的谷氨酸环化，产生高度淀粉样变性的pGluAβ(3-40/42)肽。提示组织蛋白酶B和谷氨酰环酶是潜在的AD治疗新靶点。
This highlight article describes three Alzheimer’s disease (AD) presentations made at the 5th General Meeting of the International Proteolysis Society that address enzymatic mechanisms that produce neurotoxic beta-amyloid (Aβ) peptides. One group described the poor kinetic properties of the BACE 1 β-secretase for cleaving the wild-type β-secretase site in the APP found in most AD patients. They demonstrated that cathepsin D displays BACE 1-like specificity, is 280-fold more abundant in human brain than BACE 1, and pepstatin A inhibits cleavage of β-secretase site peptides by brain extracts and cathepsin D, but not by BACE 1. Nevertheless, as BACE 1 and cathepsin D show poor activity towards the wild type β-secretase site, they suggested continuing the search for additional β-secretase candidate(s). The second group reported that cathepsin B is such an alternative β-secretase candidate possessing excellent kinetic efficiency and specificity for cleaving the wild-type β-secretase site. Significantly, they demonstrated that inhibitors of cathepsin B improved memory function with reduced amyloid plaque neuropathology and decreased brain Aβ(40/42) and β-secretase activity in AD animal models expressing APP containing the wild-type β-secretase site. The third group addressed isoaspartate and pyroglutamate (pGlu) posttranslational modifications of Aβ that are present in AD brains, with evidence that cathepsin B, but not BACE 1, efficiently cleaves the wild-type β-secretase site containing isoaspartate. They also found that cyclization of N-terminal Glu by glutaminyl cyclase generates pGluAβ(3-40/42) peptides that are highly amyloidogenic. These presentations suggested that cathepsin B and glutaminyl cyclase are potential new AD therapeutic targets.