Small molecule LX2343 ameliorates cognitive deficits in AD model mice by targeting both amyloid beta production and clearance

doi:10.1038/aps.2016.80

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第三研究室

	Small molecule LX2343 ameliorates cognitive deficits in AD model mice by targeting both amyloid beta production and clearance
	Guo, Xiao-dan 1,2,3; Sun, Guang-long 1,2,3; Zhou, Ting-ting 1,2,3; Xu, Xin 1,2,3; Zhu, Zhi-yuan 1,2,3; Rukachaisirikul, Vatcharin 4; Hu, Li-hong 1,2,3; Shen, Xu1,2,3
刊名	ACTA PHARMACOLOGICA SINICA
	2016-10
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 BACE1 PI3K autophagy APP/PS1 transgenic mice cognitive deficit
ISSN号	1671-4083
DOI	10.1038/aps.2016.80
文献子类	Article
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.
资助项目	National Natural Science Foundation of China[81220108025] ; National Natural Science Foundation of China[81473141] ; National Natural Science Foundation of China[81273556] ; NSFC-TRF collaboration projects[81561148011] ; NSFC-TRF collaboration projects[DBG5980001] ; Drug Innovation Project of SIMM[CASIMM0120154035]
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
语种	英语
CSCD记录号	CSCD:5820838
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000385634300002
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275876]
专题	药理学第三研究室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上海中药现代化研究中心
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.