title: Phenotypic assays for β-amyloid in mouse embryonic stem cell-derived neurons.
abstract: Given the complex nature of Alzheimer's disease (AD), a cell-based model that recapitulates the physiological properties of the target neuronal population would be extremely valuable for discovering improved drug candidates and chemical probes to uncover disease mechanisms. We established phenotypic neuronal assays for the biogenesis and synaptic action of amyloid β peptide (Aβ) based on embryonic stem cell-derived neurons (ESNs). ESNs enriched with pyramidal neurons were robust, scalable, and amenable to a small-molecule screening assay, overcoming the apparent limitations of neuronal models derived from human pluripotent cells. Small-molecule screening of clinical compounds identified four compounds capable of reducing Aβ levels in ESNs derived from the Tg2576 mouse model of AD. Our approach is therefore highly suitable for phenotypic screening in AD drug discovery and has the potential to identify therapeutic candidates with improved efficacy and safety potential.
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Laura Beth J
authors.initials: LB
authors.lastname: McIntire
authors.forename: Natalie
authors.initials: N
authors.lastname: Landman
authors.forename: Min Suk
authors.initials: MS
authors.lastname: Kang
authors.forename: Gina M
authors.initials: GM
authors.lastname: Finan
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Hwang
authors.forename: Ann Z
authors.initials: AZ
authors.lastname: Moore
authors.forename: Lydia S
authors.initials: LS
authors.lastname: Park
authors.forename: Chyuan-Sheng
authors.initials: CS
authors.lastname: Lin
authors.forename: Tae-Wan
authors.initials: TW
authors.lastname: Kim
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D053595:Embryonic Stem Cells / Q000166:cytology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D013569:Synapses / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D053829:Amyloid Precursor Protein Secretases
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