iPSC-Based Compound Screening and In Vitro Trials Identify a Synergistic Anti-amyloid β Combination for Alzheimer's Disease

Cell Rep. 2017 Nov 21;21(8):2304-2312. doi: 10.1016/j.celrep.2017.10.109.


In the process of drug development, in vitro studies do not always adequately predict human-specific drug responsiveness in clinical trials. Here, we applied the advantage of human iPSC-derived neurons, which offer human-specific drug responsiveness, to screen and evaluate therapeutic candidates for Alzheimer's disease (AD). Using AD patient neurons with nearly 100% purity from iPSCs, we established a robust and reproducible assay for amyloid β peptide (Aβ), a pathogenic molecule in AD, and screened a pharmaceutical compound library. We acquired 27 Aβ-lowering screen hits, prioritized hits by chemical structure-based clustering, and selected 6 leading compounds. Next, to maximize the anti-Aβ effect, we selected a synergistic combination of bromocriptine, cromolyn, and topiramate as an anti-Aβ cocktail. Finally, using neurons from familial and sporadic AD patients, we found that the cocktail showed a significant and potent anti-Aβ effect on patient cells. This human iPSC-based platform promises to be useful for AD drug development.

Keywords: Alzheimer’s disease; amyloid β; anti-Aβ cocktail; chemical clustering; compound screening; drug repositioning; in vitro trial; patient iPS cells.

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / immunology
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / immunology*
  • Amyloid beta-Protein Precursor / immunology
  • Drug Evaluation, Preclinical / methods
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Neurons / pathology*


  • APP protein, human
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor