Phenotypic Screening Identifies Modulators of Amyloid Precursor Protein Processing in Human Stem Cell Models of Alzheimer's Disease.

Autor:	Brownjohn PW; The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK., Smith J; The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK., Portelius E; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, 431 80 Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 431 80 Mölndal, Sweden., Serneels L; VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center for Human Genetics (CME), Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven (KU Leuven), 3000 Leuven, Belgium., Kvartsberg H; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, 431 80 Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 431 80 Mölndal, Sweden., De Strooper B; VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center for Human Genetics (CME), Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven (KU Leuven), 3000 Leuven, Belgium; Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK., Blennow K; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, 431 80 Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 431 80 Mölndal, Sweden., Zetterberg H; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, 431 80 Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 431 80 Mölndal, Sweden; Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK., Livesey FJ; The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK. Electronic address: rick@gurdon.cam.ac.uk.
Jazyk:	angličtina
Zdroj:	Stem cell reports [Stem Cell Reports] 2017 Apr 11; Vol. 8 (4), pp. 870-882. Date of Electronic Publication: 2017 Mar 09.
DOI:	10.1016/j.stemcr.2017.02.006
Abstrakt:	Human stem cell models have the potential to provide platforms for phenotypic screens to identify candidate treatments and cellular pathways involved in the pathogenesis of neurodegenerative disorders. Amyloid precursor protein (APP) processing and the accumulation of APP-derived amyloid β (Aβ) peptides are key processes in Alzheimer's disease (AD). We designed a phenotypic small-molecule screen to identify modulators of APP processing in trisomy 21/Down syndrome neurons, a complex genetic model of AD. We identified the avermectins, commonly used as anthelmintics, as compounds that increase the relative production of short Aβ peptides at the expense of longer, potentially more toxic peptides. Further studies demonstrated that this effect is not due to an interaction with the core γ-secretase responsible for Aβ production. This study demonstrates the feasibility of phenotypic drug screening in human stem cell models of Alzheimer-type dementia, and points to possibilities for indirectly modulating APP processing, independently of γ-secretase modulation. (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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