title: APP processing in human pluripotent stem cell-derived neurons is resistant to NSAID-based γ-secretase modulation.
abstract: Increasing evidence suggests that elevated Aβ42 fractions in the brain cause Alzheimer's disease (AD). Although γ-secretase modulators (GSMs), including a set of nonsteroidal anti-inflammatory drugs (NSAIDs), were found to lower Aβ42 in various model systems, NSAID-based GSMs proved to be surprisingly inefficient in human clinical trials. Reasoning that the nonhuman and nonneuronal cells typically used in pharmaceutical compound validation might not adequately reflect the drug responses of human neurons, we used human pluripotent stem cell-derived neurons from AD patients and unaffected donors to explore the efficacy of NSAID-based γ-secretase modulation. We found that pharmaceutically relevant concentrations of these GSMs that are clearly efficacious in conventional nonneuronal cell models fail to elicit any effect on Aβ42/Aß40 ratios in human neurons. Our work reveals resistance of human neurons to NSAID-based γ-secretase modulation, highlighting the need to validate compound efficacy directly in the human cell type affected by the respective disease.
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn and Hertie Foundation, 53127 Bonn, Germany.
authors.forename: Jerome
authors.initials: J
authors.lastname: Mertens
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn and Hertie Foundation, 53127 Bonn, Germany ; Life&Brain GmbH, 53127 Bonn, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Stüber
authors.affiliation: Department of Neurology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Wunderlich
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn and Hertie Foundation, 53127 Bonn, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Ladewig
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn and Hertie Foundation, 53127 Bonn, Germany.
authors.forename: Jaideep C
authors.initials: JC
authors.lastname: Kesavan
authors.affiliation: Department of Neurology, University Hospitals Leuven, 3000 Leuven, Belgium ; Laboratory for Cognitive Neurology, Department of Neurosciences, University of Leuven, 3000 Leuven, Belgium.
authors.forename: Rik
authors.initials: R
authors.lastname: Vandenberghe
authors.affiliation: Department of Old Age Psychiatry, University Hospitals Leuven, 3000 Leuven, Belgium.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Vandenbulcke
authors.affiliation: Department of Neurology, University Hospitals Leuven, 3000 Leuven, Belgium ; Laboratory for Cognitive Neurology, Department of Neurosciences, University of Leuven, 3000 Leuven, Belgium ; Vesalius Research Center, VIB, 3000 Leuven, Belgium.
authors.forename: Philip
authors.initials: P
authors.lastname: van Damme
authors.affiliation: Department of Neurology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Walter
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn and Hertie Foundation, 53127 Bonn, Germany ; Life&Brain GmbH, 53127 Bonn, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Brüstle
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn and Hertie Foundation, 53127 Bonn, Germany ; Life&Brain GmbH, 53127 Bonn, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Koch
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002454:Cell Differentiation; D002460:Cell Line; D053595:Embryonic Stem Cells; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D010446:Peptide Fragments / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases