Small molecule LX2343 ameliorates cognitive deficits in AD model mice by targeting both amyloid β production and clearance
文献类型：期刊论文
| 作者 | Guo Xiaodan2; Sun Guanglong2; Zhou Tingting2; Xu Xin2; Zhu Zhiyuan2; Rukachaisirikul Vatcharin1; Hu Lihong2; Shen Xu2
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| 刊名 | 中国药理学报：英文版
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| 出版日期 | 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 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/293655]  |
| 专题 | 中国科学院上海药物研究所 |
| 作者单位 | 1.宋卡王子大学 2.中国科学院上海药物研究所 |
| 推荐引用方式 GB/T 7714 | Guo Xiaodan,Sun Guanglong,Zhou Tingting,et al. Small molecule LX2343 ameliorates cognitive deficits in AD model mice by targeting both amyloid β production and clearance[J]. 中国药理学报：英文版,2016,000(010):1281. |
| APA | Guo Xiaodan.,Sun Guanglong.,Zhou Tingting.,Xu Xin.,Zhu Zhiyuan.,...&Shen Xu.(2016).Small molecule LX2343 ameliorates cognitive deficits in AD model mice by targeting both amyloid β production and clearance.中国药理学报：英文版,000(010),1281. |
| MLA | Guo Xiaodan,et al."Small molecule LX2343 ameliorates cognitive deficits in AD model mice by targeting both amyloid β production and clearance".中国药理学报：英文版 000.010(2016):1281. |
入库方式： OAI收割
来源：上海药物研究所
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