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
Volume9
Issue4
Pagination1221-1233
Date Published2017 Oct 10
ISSN2213-6711
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
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.

DOI10.1016/j.stemcr.2017.08.019
Alternate JournalStem Cell Reports
PubMed ID28966121
PubMed Central IDPMC5639430
Grant ListK01 AG046374 / AG / NIA NIH HHS / United States