Targeting the γ-/β-secretase interaction reduces β-amyloid generation and ameliorates Alzheimer's disease-related pathogenesis

被引：31

作者：

Cui, Jin ^{[1
,2
]}

Wang, Xiaoyin ^{[3
]}

Li, Xiaohang ^{[1
,2
]}

Wang, Xin ^{[1
,2
]}

Zhang, Chenlu ^{[3
]}

Li, Wei ^{[1
,2
]}

Zhang, Yangming ^{[3
]}

Gu, Haifeng ^{[3
]}

Xie, Xin ^{[3
]}

Nan, Fajun ^{[3
]}

Zhao, Jian ^{[1
,2
,5
]}

Pei, Gang ^{[1
,2
,4
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Cell Biol, Shanghai, Peoples R China

[2] Univ Chinese Acad Sci, Chinese Acad Sci, Grad Sch, Shanghai, Peoples R China

[3] Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai, Peoples R China

[4] Tongji Univ, Collaborat Innovat Ctr Brain Sci, Sch Life Sci & Technol, Shanghai, Peoples R China

[5] Tongji Univ, Shanghai East Hosp, Sch Med, Translat Med Ctr Stem Cell Therapy, Shanghai, Peoples R China

来源：

CELL DISCOVERY | 2015年 / 1卷

基金：

中国国家自然科学基金;

关键词：

PS1/BACE1; interaction; A beta generation; Alzheimer's disease; PROTEIN-CLEAVING ENZYME-1; PRECURSOR PROTEIN; PHOTOAFFINITY PROBES; CELL-SURFACE; MOUSE MODEL; PRESENILIN-1; BACE1; COMPLEX; PURIFICATION; SPECIFICITY;

D O I：

10.1038/celldisc.2015.21

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Despite decades of intense global effort, no disease-modifying drugs for Alzheimer's disease have emerged. Molecules targeting catalytic activities of gamma-secretase or beta-site APP-cleaving enzyme 1 (BACE1) have been beset by undesired side effects. We hypothesized that blocking the interaction between BACE1 and gamma-secretase subunit presenilin-1 (PS1) might offer an alternative strategy to selectively suppress A beta generation. Through high-throughput screening, we discovered that 3-alpha-akebonoic acid (3AA) interferes with PS1/BACE1 interaction and reduces A beta production. Structural analogs of 3AA were systematically synthesized and the functional analog XYT472B was identified. Photo-activated crosslinking and biochemical competition assays showed that 3AA and XYT472B bind to PS1, interfere with PS1/BACE1 interaction, and reduce A beta production, whereas sparing secretase activities. Furthermore, treatment of APP/PS1 mice with XYT472B alleviated cognitive dysfunction and A beta-related pathology. Together, our results indicate that chemical interference of PS1/BACE1 interaction is a promising strategy for Alzheimer's disease therapeutics.

引用

页数：18

共 61 条

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