title: Small molecule LX2343 ameliorates cognitive deficits in AD model mice by targeting both amyloid β production and clearance.
abstract: OBJECTIVE
  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)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 Aβ accumulation in HEK293-APPswand 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/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 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 μmol/L) dose-dependently decreased Aβ accumulation in HEK293-APPswand 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 APPThr668phosphorylation, thus inhibiting APP cleavage on one hand, and inhibiting BACE1 enzymatic activity with an IC50value 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 autophagy, 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.
  
  
  CONCLUSIONS
  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.
authors: CAS Key Laboratory of Receptor Research.|State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Xiao-Dan
authors: XD
authors: Guo
authors: CAS Key Laboratory of Receptor Research.|State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Guang-Long
authors: GL
authors: Sun
authors: CAS Key Laboratory of Receptor Research.|State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Ting-Ting
authors: TT
authors: Zhou
authors: CAS Key Laboratory of Receptor Research.|State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Xin
authors: X
authors: Xu
authors: CAS Key Laboratory of Receptor Research.|State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Zhi-Yuan
authors: ZY
authors: Zhu
authors: Department of Chemistry, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand.
authors: Vatcharin
authors: V
authors: Rukachaisirikul
authors: CAS Key Laboratory of Receptor Research.|State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Li-Hong
authors: LH
authors: Hu
authors: CAS Key Laboratory of Receptor Research.|State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Xu
authors: X
authors: Shen
mesh_terms: D000081:Acetamides / Q000494:pharmacology / Q000627:therapeutic use*; D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D004331:Drosophila melanogaster; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018697:Nootropic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D058225:Plaque, Amyloid / Q000139:chemically induced / Q000188:drug therapy*; D013311:Streptozocin; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000081:Acetamides; D016229:Amyloid beta-Peptides; C000613881:LX2343; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D013449:Sulfonamides; D013311:Streptozocin