Purification and cloning of amyloid precursor protein β-secretase from human brain

被引：1421

作者：

Sinha, S ^{[1
]}

Anderson, JP ^{[1
]}

Barbour, R ^{[1
]}

Basi, GS ^{[1
]}

Caccavello, R ^{[1
]}

Davis, D ^{[1
]}

Doan, M ^{[1
]}

Dovey, HF ^{[1
]}

Frigon, N ^{[1
]}

Hong, J ^{[1
]}

Jacobson-Croak, K ^{[1
]}

Jewett, N ^{[1
]}

Keim, P ^{[1
]}

Knops, J ^{[1
]}

Lieberburg, I ^{[1
]}

Power, M ^{[1
]}

Tan, H ^{[1
]}

Tatsuno, G ^{[1
]}

Tung, J ^{[1
]}

Schenk, D ^{[1
]}

Seubert, P ^{[1
]}

Suomensaari, SM ^{[1
]}

Wang, SW ^{[1
]}

Walker, D ^{[1
]}

Zhao, J ^{[1
]}

McConlogue, L ^{[1
]}

John, V ^{[1
]}

机构：

[1] Elan Pharmaceut, S San Francisco, CA 94080 USA

来源：

NATURE | 1999年 / 402卷 / 6761期

关键词：

D O I：

10.1038/990114

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Proteolytic processing of the amyloid precursor protein (APP) generates amyloid beta (A beta) peptide, which is thought to be causal for the pathology and subsequent cognitive decline in Alzheimer's disease. Cleavage by beta-secretase at the amino terminus of the A beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP(1), and a corresponding cell-associated carboxy-terminal fragment. Cleavage of the C-terminal fragment by gamma-secretase(s) leads to the formation of A beta. The pathogenic mutation K670M671 --> N670L671 at the beta-secretase cleavage site in APP(2), which was discovered in a Swedish family with familial Alzheimer's disease, leads to increased beta-secretase cleavage of the mutant substrate(3). Here we describe a membrane-bound enzyme activity that cleaves full-length APP at the beta-secretase cleavage site, and find it to be the predominant beta-cleavage activity in human brain. We have purified this enzyme activity to homogeneity from human brain using a new substrate analogue inhibitor of the enzyme activity, and show that the purified enzyme has all the properties predicted for beta-secretase. Cloning and expression of the enzyme reveals that human brain beta-secretase is a new membrane-bound aspartic proteinase.

引用

页码：537 / 540

页数：4

共 12 条

[1] MUTATION OF THE BETA-AMYLOID PRECURSOR PROTEIN IN FAMILIAL ALZHEIMERS-DISEASE INCREASES BETA-PROTEIN PRODUCTION [J].