Yamazaki T, Ihara Y
Department of Neuropathology, Faculty of Medicine, University of Tokyo, Japan.
Neurobiol Aging. 1998 Jan-Feb;19(1 Suppl):S77-9. doi: 10.1016/s0197-4580(98)00031-1.
Amyloid beta-protein (Abeta) is classified into two subspecies defined by its C-terminal length, designated Abeta40 and Abeta42. Although Abeta42 accounts for only approximately 10% of secreted Abeta, this particular species is the most dominant species in Abeta deposits in Alzheimer's disease (AD) and normal aged brains and appears to be the initially deposited species. Secretion levels of Abeta42 have been shown to increase in patients affected by any form of early-onset familial AD. Thus, the suppression of Abeta42 production or secretion could be a therapeutic strategy for AD. In this study, we examined whether protease inhibition affects the Abeta42 secretion ratio (Abeta42: total Abeta). Using specific inhibitors, we determined that the inhibition of calpain but not proteasome induces an increased Abeta42 secretion in cultured cells. These data suggest that calpain differentially affects the gamma-secretases generating Abeta40 and Abeta42 and indicate the possibility of developing compounds that reduce Abeta42 production and secretion though this pathway.
淀粉样β蛋白（Aβ）根据其C末端长度分为两个亚类，分别称为Aβ40和Aβ42。尽管Aβ42仅占分泌型Aβ的约10%，但在阿尔茨海默病（AD）和正常老年大脑的Aβ沉积物中，这一特定类型却是最主要的，并且似乎是最初沉积的类型。已表明，任何形式的早发性家族性AD患者的Aβ42分泌水平都会升高。因此，抑制Aβ42的产生或分泌可能是治疗AD的一种策略。在本研究中，我们检测了蛋白酶抑制是否会影响Aβ42分泌率（Aβ42：总Aβ）。使用特异性抑制剂，我们确定抑制钙蛋白酶而非蛋白酶体可诱导培养细胞中Aβ42分泌增加。这些数据表明，钙蛋白酶对生成Aβ40和Aβ42的γ-分泌酶有不同影响，并提示有可能开发出通过该途径减少Aβ42产生和分泌的化合物。
