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

TitleScalable Production of iPSC-Derived Human Neurons to Identify Tau-Lowering Compounds by High-Content Screening.
Publication TypeJournal Article
Year of Publication2017
AuthorsWang C, Ward ME, Chen R, Liu K, Tracy TE, Chen X, Xie M, Sohn PDongmin, Ludwig C, Meyer-Franke A, Karch CM, Ding S, Gan L
JournalStem Cell Reports
Date Published2017 10 10
KeywordsCell Differentiation, Cell Line, Cell Survival, Cells, Cultured, Drug Discovery, Drug Evaluation, Preclinical, Gene Expression, Gene Expression Regulation, Gene Order, Genetic Vectors, Glutamine, High-Throughput Screening Assays, Humans, Induced Pluripotent Stem Cells, Membrane Potentials, Neurons, tau Proteins

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.

Alternate JournalStem Cell Reports
PubMed ID28966121
PubMed Central IDPMC5639430
Grant ListK01 AG046374 / AG / NIA NIH HHS / United States
R01 AG036884 / AG / NIA NIH HHS / United States
R01 AG051390 / AG / NIA NIH HHS / United States
K08 EY023610 / EY / NEI NIH HHS / United States