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Scalable Production of iPSC-Derived Human Neurons to Identify Tau-Lowering Compounds by High-Content Screening.

  • Author(s): Wang, Chao;
  • Ward, Michael E;
  • Chen, Robert;
  • Liu, Kai;
  • Tracy, Tara E;
  • Chen, Xu;
  • Xie, Min;
  • Sohn, Peter Dongmin;
  • Ludwig, Connor;
  • Meyer-Franke, Anke;
  • Karch, Celeste M;
  • Ding, Sheng;
  • Gan, Li
  • et al.
Abstract

Lowering total tau levels is an attractive therapeutic strategy for Alzheimer's disease and other tauopathies. High-throughput screening in neurons derived from human induced pluripotent stem cells (iPSCs) is a powerful tool to identify tau-targeted therapeutics. However, such screens have been hampered by heterogeneous neuronal production, high cost and low yield, and multi-step differentiation procedures. We engineered an isogenic iPSC line that harbors an inducible neurogenin 2 transgene, a transcription factor that rapidly converts iPSCs to neurons, integrated at the AAVS1 locus. Using a simplified two-step protocol, we differentiated these iPSCs into cortical glutamatergic neurons with minimal well-to-well variability. We developed a robust high-content screening assay to identify tau-lowering compounds in LOPAC and identified adrenergic receptors agonists as a class of compounds that reduce endogenous human tau. These techniques enable the use of human neurons for high-throughput screening of drugs to treat neurodegenerative disease.

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