Learning by Failing: Ideas and Concepts to Tackle γ-Secretases in Alzheimer's Disease and Beyond

被引：99

作者：

De Strooper, Bart ^{[1
,2
]}

Gutierrez, Lucia Chavez ^{[1
,2
]}

机构：

[1] Vlaams Inst Biotechnol, VIB Ctr Biol Dis, BE-3000 Leuven, Belgium

[2] Katholieke Univ Leuven, Lab Res Neurodegenerat Dis, Ctr Human Genet, BE-3000 Leuven, Belgium

来源：

ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 55 | 2015年 / 55卷

基金：

欧洲研究理事会;

关键词：

intramembrane proteolysis; structure; modulators; therapy; clinical trials; AMYLOID-BETA-PEPTIDE; MILD COGNITIVE IMPAIRMENT; TRANSMEMBRANE DOMAIN 1; C-TERMINAL FRAGMENT; A-BETA; CATALYTIC PORE; PRESENILIN ENDOPROTEOLYSIS; ACTIVATING PROTEIN; MISSENSE MUTATIONS; IN-VIVO;

D O I：

10.1146/annurev-pharmtox-010814-124309

中图分类号：

R9 [药学];

学科分类号：

100702 [药剂学];

摘要：

gamma-Secretases are a group of widely expressed, intramembrane-cleaving proteases involved in many physiological processes. Their clinical relevance comes from their involvement in Alzheimer's disease, cancer, and other disorders. A clinical trial with the wide-spectrum.-secretase inhibitor sema-gacestat has, however, demonstrated that global inhibition of all gamma-secretases causes serious toxicity. Evolving insights suggest that selective inhibition of one of these proteases, or more subtle modulation of gamma-secretases by stimulating their carboxypeptidase-like activity but sparing their endopeptidase activity, are potentially highly interesting approaches. The rapidly growing knowledge of regulation, assembly, and specificity of these intriguing protein complexes and the potential advent of high-resolution structural information could dramatically change the perspective on safe and efficacious.-secretase inhibition in various disorders.

引用

页码：419 / 437

页数：19

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