APP Processing in Human Pluripotent Stem Cell-Derived Neurons Is Resistant to NSAID-Based γ-Secretase Modulation
Identifieur interne : 000339 ( Main/Exploration ); précédent : 000338; suivant : 000340APP Processing in Human Pluripotent Stem Cell-Derived Neurons Is Resistant to NSAID-Based γ-Secretase Modulation
Auteurs : Jerome Mertens [Allemagne] ; Kathrin Stüber [Allemagne] ; Patrick Wunderlich [Allemagne] ; Julia Ladewig [Allemagne] ; Jaideep C. Kesavan [Allemagne] ; Rik Vandenberghe [Belgique] ; Mathieu Vandenbulcke [Belgique] ; Philip Van Damme [Belgique] ; Jochen Walter [Allemagne] ; Oliver Brüstle [Allemagne] ; Philipp Koch [Allemagne]Source :
- Stem Cell Reports [ 2213-6711 ] ; 2013.
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.
Url:
DOI: 10.1016/j.stemcr.2013.10.011
PubMed: 24371804
PubMed Central: 3871388
Affiliations:
- Allemagne, Belgique
- District de Cologne, Province du Brabant flamand, Rhénanie-du-Nord-Westphalie
- Bonn, Louvain
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Neurobiology, University of Bonn and Hertie Foundation, 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Stuber, Kathrin" sort="Stuber, Kathrin" uniqKey="Stuber K" first="Kathrin" last="Stüber">Kathrin Stüber</name><affiliation wicri:level="3"><nlm:aff id="aff1">Institute of Reconstructive Neurobiology, University of Bonn and Hertie Foundation, 53127 Bonn, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Reconstructive Neurobiology, University of Bonn and Hertie Foundation, 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="aff2">Life&Brain GmbH, 53127 Bonn, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Life&Brain GmbH, 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Wunderlich, Patrick" sort="Wunderlich, Patrick" uniqKey="Wunderlich P" first="Patrick" last="Wunderlich">Patrick Wunderlich</name><affiliation wicri:level="3"><nlm:aff id="aff3">Department of Neurology, University of Bonn, 53127 Bonn, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Neurology, University of Bonn, 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Ladewig, Julia" sort="Ladewig, Julia" uniqKey="Ladewig J" first="Julia" last="Ladewig">Julia Ladewig</name><affiliation wicri:level="3"><nlm:aff id="aff1">Institute of Reconstructive Neurobiology, University of Bonn and Hertie Foundation, 53127 Bonn, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Reconstructive Neurobiology, University of Bonn and Hertie Foundation, 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Kesavan, Jaideep C" sort="Kesavan, Jaideep C" uniqKey="Kesavan J" first="Jaideep C." last="Kesavan">Jaideep C. Kesavan</name><affiliation wicri:level="3"><nlm:aff id="aff1">Institute of Reconstructive Neurobiology, University of Bonn and Hertie Foundation, 53127 Bonn, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Reconstructive Neurobiology, University of Bonn and Hertie Foundation, 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Vandenberghe, Rik" sort="Vandenberghe, Rik" uniqKey="Vandenberghe R" first="Rik" last="Vandenberghe">Rik Vandenberghe</name><affiliation wicri:level="3"><nlm:aff id="aff4">Department of Neurology, University Hospitals Leuven, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Neurology, University Hospitals Leuven, 3000 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="aff5">Laboratory for Cognitive Neurology, Department of Neurosciences, University of Leuven, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory for Cognitive Neurology, Department of Neurosciences, University of Leuven, 3000 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="Vandenbulcke, Mathieu" sort="Vandenbulcke, Mathieu" uniqKey="Vandenbulcke M" first="Mathieu" last="Vandenbulcke">Mathieu Vandenbulcke</name><affiliation wicri:level="3"><nlm:aff id="aff6">Department of Old Age Psychiatry, University Hospitals Leuven, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Old Age Psychiatry, University Hospitals Leuven, 3000 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="Van Damme, Philip" sort="Van Damme, Philip" uniqKey="Van Damme P" first="Philip" last="Van Damme">Philip Van Damme</name><affiliation wicri:level="3"><nlm:aff id="aff4">Department of Neurology, University Hospitals Leuven, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Neurology, University Hospitals Leuven, 3000 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="aff5">Laboratory for Cognitive Neurology, Department of Neurosciences, University of Leuven, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory for Cognitive Neurology, Department of Neurosciences, University of Leuven, 3000 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="aff7">Vesalius Research Center, VIB, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Vesalius Research Center, VIB, 3000 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="Walter, Jochen" sort="Walter, Jochen" uniqKey="Walter J" first="Jochen" last="Walter">Jochen Walter</name><affiliation wicri:level="3"><nlm:aff id="aff3">Department of Neurology, University of Bonn, 53127 Bonn, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Neurology, University of Bonn, 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Brustle, Oliver" sort="Brustle, Oliver" uniqKey="Brustle O" first="Oliver" last="Brüstle">Oliver Brüstle</name><affiliation wicri:level="3"><nlm:aff id="aff1">Institute of Reconstructive Neurobiology, University of Bonn and Hertie Foundation, 53127 Bonn, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Reconstructive Neurobiology, University of Bonn and Hertie Foundation, 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="aff2">Life&Brain GmbH, 53127 Bonn, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Life&Brain GmbH, 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Koch, Philipp" sort="Koch, Philipp" uniqKey="Koch P" first="Philipp" last="Koch">Philipp Koch</name><affiliation wicri:level="3"><nlm:aff id="aff1">Institute of Reconstructive Neurobiology, University of Bonn and Hertie Foundation, 53127 Bonn, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Reconstructive Neurobiology, University of Bonn and Hertie Foundation, 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="aff2">Life&Brain GmbH, 53127 Bonn, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Life&Brain GmbH, 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author></analytic><series><title level="j">Stem Cell Reports</title><idno type="eISSN">2213-6711</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Summary</title><p>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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Bannwarth, B" uniqKey="Bannwarth B">B. Bannwarth</name></author><author><name sortKey="Netter, P" uniqKey="Netter P">P. Netter</name></author><author><name sortKey="Lapicque, F" uniqKey="Lapicque F">F. Lapicque</name></author><author><name sortKey="Pere, P" uniqKey="Pere P">P. Péré</name></author><author><name sortKey="Thomas, P" uniqKey="Thomas P">P. Thomas</name></author><author><name sortKey="Gaucher, A" uniqKey="Gaucher A">A. Gaucher</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Blennow, K" uniqKey="Blennow K">K. Blennow</name></author><author><name sortKey="Zetterberg, H" uniqKey="Zetterberg H">H. 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Kornhuber</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Allemagne</li><li>Belgique</li></country><region><li>District de Cologne</li><li>Province du Brabant flamand</li><li>Rhénanie-du-Nord-Westphalie</li></region><settlement><li>Bonn</li><li>Louvain</li></settlement></list><tree><country name="Allemagne"><region name="Rhénanie-du-Nord-Westphalie"><name sortKey="Mertens, Jerome" sort="Mertens, Jerome" uniqKey="Mertens J" first="Jerome" last="Mertens">Jerome Mertens</name></region><name sortKey="Brustle, Oliver" sort="Brustle, Oliver" uniqKey="Brustle O" first="Oliver" last="Brüstle">Oliver Brüstle</name><name sortKey="Brustle, Oliver" sort="Brustle, Oliver" uniqKey="Brustle O" first="Oliver" last="Brüstle">Oliver Brüstle</name><name sortKey="Kesavan, Jaideep C" sort="Kesavan, Jaideep C" uniqKey="Kesavan J" first="Jaideep C." last="Kesavan">Jaideep C. Kesavan</name><name sortKey="Koch, Philipp" sort="Koch, Philipp" uniqKey="Koch P" first="Philipp" last="Koch">Philipp Koch</name><name sortKey="Koch, Philipp" sort="Koch, Philipp" uniqKey="Koch P" first="Philipp" last="Koch">Philipp Koch</name><name sortKey="Ladewig, Julia" sort="Ladewig, Julia" uniqKey="Ladewig J" first="Julia" last="Ladewig">Julia Ladewig</name><name sortKey="Stuber, Kathrin" sort="Stuber, Kathrin" uniqKey="Stuber K" first="Kathrin" last="Stüber">Kathrin Stüber</name><name sortKey="Stuber, Kathrin" sort="Stuber, Kathrin" uniqKey="Stuber K" first="Kathrin" last="Stüber">Kathrin Stüber</name><name sortKey="Walter, Jochen" sort="Walter, Jochen" uniqKey="Walter J" first="Jochen" last="Walter">Jochen Walter</name><name sortKey="Wunderlich, Patrick" sort="Wunderlich, Patrick" uniqKey="Wunderlich P" first="Patrick" last="Wunderlich">Patrick Wunderlich</name></country><country name="Belgique"><region name="Province du Brabant flamand"><name sortKey="Vandenberghe, Rik" sort="Vandenberghe, Rik" uniqKey="Vandenberghe R" first="Rik" last="Vandenberghe">Rik Vandenberghe</name></region><name sortKey="Van Damme, Philip" sort="Van Damme, Philip" uniqKey="Van Damme P" first="Philip" last="Van Damme">Philip Van Damme</name><name sortKey="Van Damme, Philip" sort="Van Damme, Philip" uniqKey="Van Damme P" first="Philip" last="Van Damme">Philip Van Damme</name><name sortKey="Van Damme, Philip" sort="Van Damme, Philip" uniqKey="Van Damme P" first="Philip" last="Van Damme">Philip Van Damme</name><name sortKey="Vandenberghe, Rik" sort="Vandenberghe, Rik" uniqKey="Vandenberghe R" first="Rik" last="Vandenberghe">Rik Vandenberghe</name><name sortKey="Vandenbulcke, Mathieu" sort="Vandenbulcke, Mathieu" uniqKey="Vandenbulcke M" first="Mathieu" last="Vandenbulcke">Mathieu Vandenbulcke</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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