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
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
收藏
页数:18
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