Pharmacological knock-down of the presenilin 1 heterodimer by a novel gamma -secretase inhibitor: implications for presenilin biology.
Pharmacological knock-down of the presenilin 1 heterodimer by a novel gamma -secretase inhibitor: implications for presenilin biology.
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一种新型γ-分泌酶抑制剂对早老素1异二聚体的药理学敲低：对早老素生物学的影响。
DOI：
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发表时间：
2001
影响因子：
4.8
通讯作者：
M. Shearman
中科院分区：
文献类型：
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作者：
D. Beher;Jonathan D Wrigley;A. Nadin;G. Evin;Colin L. Masters;Timothy Harrison;J. Castro;M. Shearman
β-淀粉样前体蛋白被γ-分泌酶膜内切割是产生淀粉样β肽的最终加工事件，淀粉样β肽被认为是阿尔茨海默病的病原体。早老素基因中的错义突变与早发性阿尔茨海默病共分离，最近，早老素和γ-分泌酶的身份之间的密切生化联系已经建立。在这里，我们描述了第一次，某些有效的γ-分泌酶抑制剂能够干扰早老素1（PS1）的内蛋白水解加工。此外，我们鉴定了一种新型γ-分泌酶抑制剂，[1 S-苄基-4R-[1-（5-环己基-2-氧代-2，3-二氢-1H-苯并[e][1，4]二氮杂卓-3（R，S）-基氨基甲酰基）-S-乙基氨基甲酰基]-2R-羟基-5-苯基-戊基]-氨基甲酸叔丁酯（CBAP），其不仅与PS1发生物理相互作用，而且在长期治疗后产生PS1片段的“药理学敲低”。这表明所观察到的全长PS1的积累是由其内蛋白水解的直接抑制引起的。随后使用CBAP作为生物学工具，以增加全长PS1水平的情况下，外源PS1的表达提供了证据，野生型PS1内切蛋白水解是不需要的PS1/γ-分泌酶复合物组装或运输。此外，在基于细胞的系统中，CBAP不完全概括PS1功能丧失表型。尽管CBAP抑制Notch受体的β-淀粉样前体蛋白裂解和S3裂解，但未观察到Trk受体成熟受损。
Intramembranous cleavage of the beta-amyloid precursor protein by gamma-secretase is the final processing event generating amyloid-beta peptides, which are thought to be causative agents for Alzheimer's disease. Missense mutations in the presenilin genes co-segregate with early-onset Alzheimer's disease, and, recently, a close biochemical linkage between presenilins and the identity of gamma-secretase has been established. Here we describe for the first time that certain potent gamma-secretase inhibitors are able to interfere with the endoproteolytic processing of presenilin 1 (PS1). In addition, we identified a novel gamma-secretase inhibitor, [1S-benzyl-4R-[1-(5-cyclohexyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3(R,S)-ylcarbamoyl)-S-ethylcarbamoyl]-2R-hydroxy-5-phenyl-pentyl]-carbamic acid tert-butyl ester (CBAP), which not only physically interacts with PS1, but upon chronic treatment produces a "pharmacological knock-down" of PS1 fragments. This indicates that the observed accumulation of full-length PS1 is caused by a direct inhibition of its endoproteolysis. The subsequent use of CBAP as a biological tool to increase full-length PS1 levels in the absence of exogenous PS1 expression has provided evidence that wild-type PS1 endoproteolysis is not required either for PS1/gamma-secretase complex assembly or trafficking. Furthermore, in cell-based systems CBAP does not completely recapitulate PS1 loss-of-function phenotypes. Even though the beta-amyloid precursor protein cleavage and the S3 cleavage of the Notch receptor are inhibited by CBAP, an impairment of Trk receptor maturation was not observed.