title: Small molecule TBTC as a new selective retinoid X receptor α agonist improves behavioral deficit in Alzheimer's disease model mice.
abstract: Alzheimer's disease (AD) is a neurodegenerative disease, which is characterized by progressive cognitive impairments. The β-amyloid (Aβ)-induced neurodegeneration is determined as the main pathogenesis of AD, and either decrease of Aβ production or increase of Aβ clearance is beneficial in the treatment of AD, while Aβ clearance regulation seems to be more attractive as a promising therapeutic strategy against AD based on the fact that the insufficient clearance of Aβ is tightly associated with the late onset of AD that is represented as the majority of AD cases. Here, we report that the small molecular compound, methyl 2-amino-6-(tert-butyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (TBTC), as a selective agonist of retinoid X receptor α (RXRα) can effectively activate the heterodimerization of RXRα with either liver X receptor α (LXRα) or peroxisome proliferator activated receptor γ (PPARγ), stimulate the expressions of the genes of apoE, ABCA1 and ABCG1, and decrease Aβ content both in cells and animal models. In addition, administration of TBTC (30mg/kg/day) in the transgenic APP-PS1 mice could also reduce the formation of senile plaques and improve the daily living activity of the mice. Therefore, our findings have suggested that TBTC might hold the potential as a drug lead compound for the treatment of AD.
authors.affiliation: School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China. Electronic address: sunyanyan1989@yeah.net.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: fjsimm@sina.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Fan
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: zzysimm@simm.ac.cn.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: rosiel630@163.com.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Guo
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: tingtingchou@126.com.
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: whduan@mail.shcnc.ac.cn.
authors.forename: Wenhu
authors.initials: W
authors.lastname: Duan
authors.affiliation: School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: xshen@simm.ac.cn.
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009425:Nesting Behavior / Q000187:drug effects; D058225:Plaque, Amyloid / Q000188:drug therapy; D047490:Retinoid X Receptor alpha / Q000819:agonists*; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D008074:Lipoproteins; D047490:Retinoid X Receptor alpha; D013876:Thiophenes; C000607801:methyl 2-amino-6-(tert-butyl)-4,5,6,7-tetrahydrobenzo(b)thiophene-3-carboxylate
keywords: Alzheimer's disease; Daily living activity; Retinoid X receptor α agonist; TBTC; β-amyloid clearance