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

doi:10.1016/j.stemcr.2017.08.019

Stem Cell Reports (Oct 2017)

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

Affiliations

Chao Wang: Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA
Michael E. Ward: Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA
Robert Chen: Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA 94158, USA
Kai Liu: Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA
Tara E. Tracy: Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA
Xu Chen: Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA
Min Xie: Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA
Peter Dongmin Sohn: Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA
Connor Ludwig: Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA 94158, USA
Anke Meyer-Franke: Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA
Celeste M. Karch: Department of Psychiatry, Washington University School of Medicine, 425 South Euclid Avenue, St. Louis, MO 63110, USA
Sheng Ding: Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA
Li Gan: Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA

DOI: https://doi.org/10.1016/j.stemcr.2017.08.019
Journal volume & issue: Vol. 9, no. 4
pp. 1221 – 1233

Abstract

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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.

Published in Stem Cell Reports

ISSN: 2213-6711 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General); Science: Biology (General)
Website: http://www.cell.com/stem-cell-reports/home

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Abstract

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