A substrate-based difluoro ketone selectively inhibits Alzheimer's γ-secretase activity
A substrate-based difluoro ketone selectively inhibits Alzheimer's γ-secretase activity
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DOI：
10.1021/jm970621b
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发表时间：
1998-01-01
影响因子：
7.3
通讯作者：
Selkoe, DJ
中科院分区：
文献类型：
--
作者：
Wolfe, MS;Citron, M;Selkoe, DJ
淀粉样蛋白斑块与阿尔茨海默病（AD）的发病密切相关，其主要蛋白质成分为淀粉样β蛋白（Aβ）。1 Aβ由39-43个氨基酸组成，来源于β-淀粉样前体蛋白（APP），一种功能未知的膜蛋白。2最近的研究结果特别表明，更疏水和高度不溶性的42个氨基酸的变体（Aβ42）在淀粉样斑块的形成和AD的发病机制中。3-5虽然Aβ42仅占细胞分泌的总Aβ的约10%（约90%是40个氨基酸的变体Aβ40），但Aβ42是弥漫性、主要为非纤维性斑块的主要蛋白组分，其先于AD特征性致密纤维性神经炎斑块的发展。6，7遗传学证据强烈暗示Aβ和Aβ42在AD病因学中的作用：迄今为止研究的与家族性早发性AD（FAD）相关的所有突变均导致Aβ42或Aβ40和A β 42的产生增加。
Amyloid plaques, invariantly associated with Alzheimer’s disease (AD), contain amyloid β-protein (Aβ) as the primary protein component. 1 The 39-43 amino acid Aβ is derived from the β-amyloid precursor protein (APP), an integral membrane protein of unknown function. 2 Recent findings particularly implicate the more hydrophobic and highly insoluble 42 amino acid variant (Aβ42) in amyloid plaque formation and in the pathogenesis of AD. 3-5 Although Aβ42 accounts for only about 10% of total Aβ secreted from cells (roughly 90% is the 40 amino acid variant Aβ40), Aβ42 is the major protein component of the diffuse, largely nonfibrillar plaques which precede the development of the dense, fibrillar neuritic plaques characteristic of AD. 6, 7 Genetic evidence strongly implicates Aβ in general and Aβ42 in particular in the etiology of AD: all mutations linked to familial early-onset AD (FAD) examined to date result in increased production of Aβ42 or of both Aβ40 and