title: BMS-708163 and Nilotinib restore synaptic dysfunction in human embryonic stem cell-derived Alzheimer's disease models.
abstract: Alzheimer's disease (AD) is the most common form of dementia. Cellular AD models derived from human pluripotent stem cells are promising tools in AD research. We recently developed human embryonic stem cell-derived AD models which overexpress mutant Presenilin1 genes, and which exhibit AD phenotypes, including synaptic dysfunction. In this study, we found that our AD models showed reduced levels of RAB3A and SV2B proteins in the pre-synapses, which is a possible cause of electrophysiological abnormalities. Through the screening of chemical compounds using our AD models, we have identified Aβ peptide inhibitors which decrease the concentration of Aβ in culture supernatant. Among these, BMS-708163 and Nilotinib were found to improve the expression levels of RAB3A and SV2B proteins and to recover the electrophysiological function in our AD models. These results suggest that the AD models we developed are promising materials for the discovery of AD drugs that target the expression of pre-synaptic proteins and synaptic function.
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8501, Japan.|Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Hisae
authors.initials: H
authors.lastname: Nishioka
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Norie
authors.initials: N
authors.lastname: Tooi
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Takehisa
authors.initials: T
authors.lastname: Isobe
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8501, Japan.|Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Nakatsuji
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Aiba
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000066449:Human Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D020692:rab3 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C554092:BMS 708163; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D010069:Oxadiazoles; D011743:Pyrimidines; C489616:SV2B protein, human; D013449:Sulfonamides; D020692:rab3 GTP-Binding Proteins; C498826:nilotinib