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

doi:10.1038/celldisc.2015.21

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 国家新药筛选中心

	Targeting the gamma-/beta-secretase interaction reduces beta-amyloid generation and ameliorates Alzheimer's disease-related pathogenesis
	Cui, Jin 1,2; Wang, Xiaoyin 3; Li, Xiaohang 1,2; Wang, Xin1,2 ; Zhang, Chenlu 3; Li, Wei 1,2; Zhang, Yangming3 ; Gu, Haifeng3 ; Xie, Xin3 ; Nan, Fajun3
刊名	CELL DISCOVERY
	2015
卷号	1
关键词	PS1/BACE1 interaction A beta generation Alzheimer's disease
ISSN号	2056-5968
DOI	10.1038/celldisc.2015.21
文献子类	Article
英文摘要	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.
资助项目	National Natural Science Foundation of China[31371419] ; Ministry of Health[2012BAI10B03]
WOS研究方向	Cell Biology
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000414776800021
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276790]
专题	国家新药筛选中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Nan, Fajun
作者单位	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
推荐引用方式 GB/T 7714	Cui, Jin,Wang, Xiaoyin,Li, Xiaohang,et al. Targeting the gamma-/beta-secretase interaction reduces beta-amyloid generation and ameliorates Alzheimer's disease-related pathogenesis[J]. CELL DISCOVERY,2015,1.
APA	Cui, Jin.,Wang, Xiaoyin.,Li, Xiaohang.,Wang, Xin.,Zhang, Chenlu.,...&Pei, Gang.(2015).Targeting the gamma-/beta-secretase interaction reduces beta-amyloid generation and ameliorates Alzheimer's disease-related pathogenesis.CELL DISCOVERY,1.
MLA	Cui, Jin,et al."Targeting the gamma-/beta-secretase interaction reduces beta-amyloid generation and ameliorates Alzheimer's disease-related pathogenesis".CELL DISCOVERY 1(2015).