Title | Scalable Production of iPSC-Derived Human Neurons to Identify Tau-Lowering Compounds by High-Content Screening. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Wang 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 |
Journal | Stem Cell Reports |
Volume | 9 |
Issue | 4 |
Pagination | 1221-1233 |
Date Published | 2017 10 10 |
ISSN | 2213-6711 |
Keywords | Cell 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 |
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. |
DOI | 10.1016/j.stemcr.2017.08.019 |
Alternate Journal | Stem Cell Reports |
PubMed ID | 28966121 |
PubMed Central ID | PMC5639430 |
Grant List | K01 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 |