In vivo inhibition of Aβ production by memapsin 2 (β-secretase) inhibitors

被引：90

作者：

Chang, WP

Koelsch, G

Wong, S

Downs, D

Da, HN

Weerasena, V

Gordon, B

Devasamudram, T

Bilcer, G

Ghosh, AK

Tang, J

机构：

[1] Oklahoma Med Res Fdn, Prot Studies Program, Oklahoma City, OK 73104 USA

[2] Zapaq Inc, Oklahoma City, OK USA

[3] Univ Oklahoma, Coll Med, Oklahoma City, OK 73190 USA

[4] Oklahoma Med Res Fdn, Dept Comparat Med, Oklahoma City, OK 73104 USA

[5] Univ Illinois, Dept Chem, Chicago, IL 60680 USA

[6] Univ Oklahoma, Hlth Sci Ctr, Dept Biochem & Mol Biol, Oklahoma City, OK 73190 USA

来源：

JOURNAL OF NEUROCHEMISTRY | 2004年 / 89卷 / 06期

关键词：

Alzheimer's disease; amyloid-beta; beta-secretase; inhibition; mouse model;

D O I：

10.1111/j.1471-4159.2004.02452.x

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

We have previously reported structure-based design of memapsin 2 (beta-secretase) inhibitors with high potency. Here we show that two such inhibitors covalently linked to a 'carrier peptide' penetrated the plasma membrane in cultured cells and inhibited the production of beta-amyloid (Abeta). Intraperitoneal injection of the conjugated inhibitors in transgenic Alzheimer's mice (Tg2576) resulted in a significant decrease of Abeta level in the plasma and brain. These observations verified that memapsin 2 is a therapeutic target for Abeta reduction and also establish that transgenic mice are suitable in vivo models for the study of memapsin 2 inhibition.

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收藏

页码：1409 / 1416

页数：8

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