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

Chao Wang, Michael E. Ward, Robert Chen, Kai Liu, Tara E. Tracy, Xu Chen, Min Xie, Peter Dongmin Sohn, Connor Ludwig, Anke Meyer-Franke, Celeste M. Karch, Sheng Ding, Li Gan: Stem Cell Reports, Volume 9, Issue 4, 10 October 2017, Pages 1221-1233 Read More

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. Gan and colleagues developed a simple and scalable technology to generate a large quantity of homogeneous glutamatergic cortical neurons by engineering a neurogenin 2-expressing cassette to the AAVS1 locus of iPSCs. They developed a high-content screening assay and identified adrenergic receptor agonists as a class of compounds that lower endogenous human tau, a key pathogenic factor in Alzheimer’s disease. © 2017 The Author(s)
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Posted on November 15, 2017
Posted in: Axon Injury & Repair, HPAN, Neurodegeneration, Neurogenetics & Transcriptomics, Publications Authors: