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

Autor:	Wang C; Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA 94158, USA., Ward ME; Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA 94158, USA; National Institute of Neurological Disorders and Stroke, National Institutes of Health, 35 Convent Drive, Bethesda, MD 20892, USA., Chen R; Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA 94158, USA., Liu K; Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, CA 94158, USA., Tracy TE; Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA 94158, USA., Chen X; Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA 94158, USA., Xie M; Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, CA 94158, USA., Sohn PD; Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA 94158, USA., Ludwig C; Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA 94158, USA., Meyer-Franke A; Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA., Karch CM; Department of Psychiatry, Washington University School of Medicine, 425 South Euclid Avenue, St. Louis, MO 63110, USA., Ding S; Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, CA 94158, USA., Gan L; Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA 94158, USA. Electronic address: lgan@gladstone.ucsf.edu.
Jazyk:	angličtina
Zdroj:	Stem cell reports [Stem Cell Reports] 2017 Oct 10; Vol. 9 (4), pp. 1221-1233. Date of Electronic Publication: 2017 Sep 28.
DOI:	10.1016/j.stemcr.2017.08.019
Abstrakt:	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. (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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