Small molecule lx2343 ameliorates cognitive deficits in ad model mice by targeting both amyloid beta production and clearance | |
Guo, Xiao-dan1,2,3; Sun, Guang-long1,2,3; Zhou, Ting-ting1,2,3; Xu, Xin1,2,3; Zhu, Zhi-yuan1,2,3; Rukachaisirikul, Vatcharin4; Hu, Li-hong1,2,3; Shen, Xu1,2,3 | |
刊名 | Acta pharmacologica sinica |
2016-10-01 | |
卷号 | 37期号:10页码:1281-1297 |
关键词 | Alzheimer's disease N-(1,3-benzodioxol-5-yl)-2-[5-chloro-2-methoxy(phenylsulfonyl)anilino]acetamide (lx2343) Streptozotocin Amyloid beta Pi3k Autophagy App/ps1 transgenic mice Cognitive deficit Bace1 |
ISSN号 | 1671-4083 |
DOI | 10.1038/aps.2016.80 |
通讯作者 | Hu, li-hong(lhhu@simm.ac.cn) ; Shen, xu(xshen@mail.shcnc.ac.cn) |
英文摘要 | Aim: streptozotocin (stz) is widely used to induce oxidative damage and to impair glucose metabolism, apoptosis, and tau/a beta pathology, eventually leading to cognitive deficits in both in vitro and in vivo models of alzheimer's disease (ad). in this study, we constructed a cell-based platform using stz to induce stress conditions mimicking the complicated pathologies of ad in vitro, and evaluated the anti-amyloid effects of a small molecule, n-(1,3-benzodioxol-5-yl)-2-[5-chloro-2-methoxy(phenylsulfonyl)anilino]acetamide (lx2343) in the amelioration of cognitive deficits in ad model mice. methods: cell-based assays for screening anti-amyloid compounds were established by assessing a beta accumulation in hek293-app(sw) and cho-app cells, and a beta clearance in primary astrocytes and sh-sy5y cells after the cells were treated with stz in the presence of the test compounds. autophagic flux was observed using confocal laser scanning microscopy. app/ps1 transgenic mice were administered lx2343 (10 mg.kg(-1).d(-1), ip) for 100 d. after lx2343 administration, cognitive ability of the mice was evaluated using morris water maze test, and senile plaques in the brains were detected using thioflavine s staining. elisa assay was used to evaluate a beta and sapp beta levels, while western blot analysis was used to measure the signaling proteins in both cell and animal brains. results: lx2343 (5-20 mu mol/l) dose-dependently decreased a beta accumulation in hek293-app(sw) and cho-app cells, and promoted a beta clearance in sh-sy5y cells and primary astrocytes. the anti-amyloid effects of lx2343 were attributed to suppressing jnk-mediated app(thr668) phosphorylation, thus inhibiting app cleavage on one hand, and inhibiting bace1 enzymatic activity with an ic50 value of 11.43 +/- 0.36 mu mol/l, on the other hand. furthermore, lx2343 acted as a non-atp competitive pi3k inhibitor to negatively regulate akt/mtor signaling, thus promoting autophagy, and increasing a beta clearance. administration of lx2343 in app/ps1 transgenic mice significantly ameliorated cognitive deficits and markedly ameliorated the a beta pathology in their brains. conclusion: lx2343 ameliorates cognitive dysfunction in app/ps1 transgenic mice via both a beta production inhibition and clearance promotion, which highlights the potential of lx2343 in the treatment of ad. |
WOS关键词 | SH-SY5Y NEUROBLASTOMA-CELLS ; ALZHEIMERS-DISEASE ; MEMORY IMPAIRMENT ; THERAPEUTIC STRATEGIES ; PRECURSOR PROTEIN ; ALPHA-SECRETASE ; AUTOPHAGY ; HYPOTHESIS ; STRESS ; PHOSPHORYLATION |
WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
WOS类目 | Chemistry, Multidisciplinary ; Pharmacology & Pharmacy |
语种 | 英语 |
出版者 | ACTA PHARMACOLOGICA SINICA |
WOS记录号 | WOS:000385634300002 |
内容类型 | 期刊论文 |
URI标识 | http://www.corc.org.cn/handle/1471x/2374825 |
专题 | 中国科学院大学 |
通讯作者 | Hu, Li-hong; Shen, Xu |
作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 4.Prince Songkla Univ, Fac Sci, Dept Chem, Hat Yai 90112, Songkhla, Thailand |
推荐引用方式 GB/T 7714 | Guo, Xiao-dan,Sun, Guang-long,Zhou, Ting-ting,et al. Small molecule lx2343 ameliorates cognitive deficits in ad model mice by targeting both amyloid beta production and clearance[J]. Acta pharmacologica sinica,2016,37(10):1281-1297. |
APA | Guo, Xiao-dan.,Sun, Guang-long.,Zhou, Ting-ting.,Xu, Xin.,Zhu, Zhi-yuan.,...&Shen, Xu.(2016).Small molecule lx2343 ameliorates cognitive deficits in ad model mice by targeting both amyloid beta production and clearance.Acta pharmacologica sinica,37(10),1281-1297. |
MLA | Guo, Xiao-dan,et al."Small molecule lx2343 ameliorates cognitive deficits in ad model mice by targeting both amyloid beta production and clearance".Acta pharmacologica sinica 37.10(2016):1281-1297. |
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