title: Anti-Aβ drug screening platform using human iPS cell-derived neurons for the treatment of Alzheimer's disease.
abstract: BACKGROUND
  Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive memory and cognitive decline during middle to late adult life. The AD brain is characterized by deposition of amyloid β peptide (Aβ), which is produced from amyloid precursor protein by β- and γ-secretase (presenilin complex)-mediated sequential cleavage. Induced pluripotent stem (iPS) cells potentially provide an opportunity to generate a human cell-based model of AD that would be crucial for drug discovery as well as for investigating mechanisms of the disease.
  
  
  RESULTS
  We differentiated human iPS (hiPS) cells into neuronal cells expressing the forebrain marker, Foxg1, and the neocortical markers, Cux1, Satb2, Ctip2, and Tbr1. The iPS cell-derived neuronal cells also expressed amyloid precursor protein, β-secretase, and γ-secretase components, and were capable of secreting Aβ into the conditioned media. Aβ production was inhibited by β-secretase inhibitor, γ-secretase inhibitor (GSI), and an NSAID; however, there were different susceptibilities to all three drugs between early and late differentiation stages. At the early differentiation stage, GSI treatment caused a fast increase at lower dose (Aβ surge) and drastic decline of Aβ production.
  
  
  CONCLUSIONS
  These results indicate that the hiPS cell-derived neuronal cells express functional β- and γ-secretases involved in Aβ production; however, anti-Aβ drug screening using these hiPS cell-derived neuronal cells requires sufficient neuronal differentiation.
authors: Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
authors: Naoki
authors: N
authors: Yahata
authors: Masashi
authors: M
authors: Asai
authors: Shiho
authors: S
authors: Kitaoka
authors: Kazutoshi
authors: K
authors: Takahashi
authors: Isao
authors: I
authors: Asaka
authors: Hiroyuki
authors: H
authors: Hioki
authors: Takeshi
authors: T
authors: Kaneko
authors: Kei
authors: K
authors: Maruyama
authors: Takaomi C
authors: TC
authors: Saido
authors: Tatsutoshi
authors: T
authors: Nakahata
authors: Takashi
authors: T
authors: Asada
authors: Shinya
authors: S
authors: Yamanaka
authors: Nobuhisa
authors: N
authors: Iwata
authors: Haruhisa
authors: H
authors: Inoue
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D015153:Blotting, Western; D002460:Cell Line; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D016229:Amyloid beta-Peptides