smallmoleculelx2343amelioratescognitivedeficitsinadmodelmicebytargetingbothamyloidproductionandclearance

	smallmoleculelx2343amelioratescognitivedeficitsinadmodelmicebytargetingbothamyloidproductionandclearance
	Guo Xiaodan 1; Sun Guanglong 1; Zhou Tingting 1; Xu Xin 1; Zhu Zhiyuan 1; Rukachaisirikul Vatcharin 2; Hu Lihong 1; Shen Xu 1
刊名	actapharmacologicasinica
	2016
卷号	000 期号:010 页码:1281
关键词	Alzheimer's disease N-(1 3-benzodioxol-5-yl)-2-5-chloro-2-methoxy(phenylsulfonyl)anilinoacetamide (LX2343) streptozotocin amyloid β BACE1 PI3K autophagy APP/PS1 transgenic mice cognitive deficit
ISSN号	1671-4083
英文摘要	Aim： Streptozotocin （STZ） is widely used to induce oxidative damage and to impair glucose metabolism, apoptosis, and tau/Aβ 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）anilinoacetamide （LX2343） in the amelioration of cognitive deficits in AD model mice. Methods： Cell-based assays for screening anti-amyloid compounds were established by assessing Aβ accumulation in HEK293-APPsw and CHO-APP cells, and Aβ 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/PSltransgenic mice were administered LX2343 （10 mg.kg^-1·1^-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 Aβ and sAPPβ levels, while Western blot analysis was used to measure the signaling proteins in both cell and animal brains. Results： LX2343 （5-20 IJmol/L） dose-dependently decreased Aβ accumulation in HEK293-APPsw and CHO-APP cells, and promoted Aβ clearance in SH-SY5Y cells and primary astrocytes. The anti-amyloid effects of LX2343 were attributed to suppressing JNK-mediated APPThr668 phosphorylation, thus inhibiting APP cleavage on one hand, and inhibiting BACE1 enzymatic activity with an IC50 value of 11.43±0.36 μmol/L, on the other hand. Furthermore, LX2343 acted as a non-ATP competitive PI3K inhibitor to negatively regulate AKT/mTOR signaling, thus promoting autophag, and increasing Aβ clearance. Administration of LX2343 in APP/PS1 transgenic mice significantly ameliorated cognitive deficits and markedly ameliorated the Aβ pathology in their brains. Conclusion： LX2343 ameliorates cognitive dysfunction in APP/PS1 transgenic mice via both Aβ production inhibition and clearance promotion, which highlights the potential of LX2343 in the treatment of AD.
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/285207]
专题	中国科学院上海药物研究所
作者单位	1.中国科学院上海药物研究所 2.宋卡王子大学
推荐引用方式 GB/T 7714	Guo Xiaodan,Sun Guanglong,Zhou Tingting,et al. smallmoleculelx2343amelioratescognitivedeficitsinadmodelmicebytargetingbothamyloidproductionandclearance[J]. actapharmacologicasinica,2016,000(010):1281.
APA	Guo Xiaodan.,Sun Guanglong.,Zhou Tingting.,Xu Xin.,Zhu Zhiyuan.,...&Shen Xu.(2016).smallmoleculelx2343amelioratescognitivedeficitsinadmodelmicebytargetingbothamyloidproductionandclearance.actapharmacologicasinica,000(010),1281.
MLA	Guo Xiaodan,et al."smallmoleculelx2343amelioratescognitivedeficitsinadmodelmicebytargetingbothamyloidproductionandclearance".actapharmacologicasinica 000.010(2016):1281.