title: Phenotypic Screening Identifies Modulators of Amyloid Precursor Protein Processing in Human Stem Cell Models of Alzheimer's Disease.
abstract: 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.
authors.affiliation: The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Brownjohn
authors.affiliation: The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK.
authors.forename: James
authors.initials: J
authors.lastname: Smith
authors.affiliation: 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.
authors.forename: Erik
authors.initials: E
authors.lastname: Portelius
authors.affiliation: 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.
authors.forename: Lutgarde
authors.initials: L
authors.lastname: Serneels
authors.affiliation: 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.
authors.forename: Hlin
authors.initials: H
authors.lastname: Kvartsberg
authors.affiliation: 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.
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.affiliation: 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.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: 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.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK. Electronic address: rick@gurdon.cam.ac.uk.
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Livesey
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000871:Anthelmintics / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D004314:Down Syndrome / Q000378:metabolism / Q000473:pathology; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology; D007559:Ivermectin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D055495:Neurogenesis; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype
chemical_list: D016564:Amyloid beta-Protein Precursor; D000871:Anthelmintics; D007559:Ivermectin; C019264:avermectin; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer's disease; Down syndrome; amyloid beta; dementia; human neurons; iPSCs; ivermectin; neural stem cells; phenotypic screening; selamectin