The amyloid-β oligomer Aβ*56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation.
Identifieur interne : 000243 ( Main/Exploration ); précédent : 000242; suivant : 000244The amyloid-β oligomer Aβ*56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation.
Auteurs : Fatou Amar [États-Unis] ; Mathew A. Sherman [États-Unis] ; Travis Rush [France] ; Megan Larson [États-Unis] ; Gabriel Boyle [États-Unis] ; Liu Chang [Australie] ; Jürgen Götz [Australie] ; Alain Buisson [France] ; Sylvain E. Lesné [États-Unis]Source :
- Science signaling [ 1937-9145 ] ; 2017.
Abstract
Oligomeric forms of amyloid-forming proteins are believed to be the principal initiating bioactive species in many neurodegenerative disorders, including Alzheimer's disease (AD). Amyloid-β (Aβ) oligomers are implicated in AD-associated phosphorylation and aggregation of the microtubule-associated protein tau. To investigate the specific molecular pathways activated by different assemblies, we isolated various forms of Aβ from Tg2576 mice, which are a model for AD. We found that Aβ*56, a 56-kDa oligomer that is detected before patients develop overt signs of AD, induced specific changes in neuronal signaling. In primary cortical neurons, Aβ*56 interacted with N-methyl-d-aspartate receptors (NMDARs), increased NMDAR-dependent Ca(2+) influx, and consequently increased intracellular calcium concentrations and the activation of Ca(2+)-dependent calmodulin kinase IIα (CaMKIIα). In cultured neurons and in the brains of Tg2576 mice, activated CaMKIIα was associated with increased site-specific phosphorylation and missorting of tau, both of which are associated with AD pathology. In contrast, exposure of cultured primary cortical neurons to other oligomeric Aβ forms (dimers and trimers) did not trigger these effects. Our results indicate that distinct Aβ assemblies activate neuronal signaling pathways in a selective manner and that dissecting the molecular events caused by each oligomer may inform more effective therapeutic strategies.
DOI: 10.1126/scisignal.aal2021
PubMed: 28487416
Affiliations:
- Australie, France, États-Unis
- Auvergne-Rhône-Alpes, Minnesota, Nouvelle-Galles du Sud, Rhône-Alpes
- Grenoble, Sydney
- Université Grenoble-Alpes, Université de Sydney
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Sherman</name><affiliation wicri:level="2"><nlm:affiliation>Department of Neuroscience, University of Minnesota, Minneapolis, MN 55414, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neuroscience, University of Minnesota, Minneapolis, MN 55414</wicri:regionArea><placeName><region type="state">Minnesota</region></placeName></affiliation></author><author><name sortKey="Rush, Travis" sort="Rush, Travis" uniqKey="Rush T" first="Travis" last="Rush">Travis Rush</name><affiliation wicri:level="4"><nlm:affiliation>INSERM, U1216, Université Grenoble Alpes, Grenoble Institut des Neurosciences, BP 170, Grenoble Cedex 9, F-38042, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>INSERM, U1216, Université Grenoble Alpes, Grenoble Institut des Neurosciences, BP 170, Grenoble Cedex 9, F-38042</wicri:regionArea><placeName><region type="region" nuts="2">Auvergne-Rhône-Alpes</region><region type="old region" nuts="2">Rhône-Alpes</region><settlement type="city">Grenoble</settlement></placeName><orgName type="university">Université Grenoble-Alpes</orgName></affiliation></author><author><name sortKey="Larson, Megan" sort="Larson, Megan" uniqKey="Larson M" first="Megan" last="Larson">Megan Larson</name><affiliation wicri:level="2"><nlm:affiliation>Department of Neuroscience, University of Minnesota, Minneapolis, MN 55414, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neuroscience, University of Minnesota, Minneapolis, MN 55414</wicri:regionArea><placeName><region type="state">Minnesota</region></placeName></affiliation></author><author><name sortKey="Boyle, Gabriel" sort="Boyle, Gabriel" uniqKey="Boyle G" first="Gabriel" last="Boyle">Gabriel Boyle</name><affiliation wicri:level="2"><nlm:affiliation>Department of Neuroscience, University of Minnesota, Minneapolis, MN 55414, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neuroscience, University of Minnesota, Minneapolis, MN 55414</wicri:regionArea><placeName><region type="state">Minnesota</region></placeName></affiliation></author><author><name sortKey="Chang, Liu" sort="Chang, Liu" uniqKey="Chang L" first="Liu" last="Chang">Liu Chang</name><affiliation wicri:level="4"><nlm:affiliation>Sydney Medical School, Brain and Mind Research Institute, University of Sydney, Camperdown, Sydney, New South Wales 2050, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Sydney Medical School, Brain and Mind Research Institute, University of Sydney, Camperdown, Sydney, New South Wales 2050</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Gotz, Jurgen" sort="Gotz, Jurgen" uniqKey="Gotz J" first="Jürgen" last="Götz">Jürgen Götz</name><affiliation wicri:level="1"><nlm:affiliation>Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072</wicri:regionArea><wicri:noRegion>Queensland 4072</wicri:noRegion></affiliation></author><author><name sortKey="Buisson, Alain" sort="Buisson, Alain" uniqKey="Buisson A" first="Alain" last="Buisson">Alain Buisson</name><affiliation wicri:level="4"><nlm:affiliation>INSERM, U1216, Université Grenoble Alpes, Grenoble Institut des Neurosciences, BP 170, Grenoble Cedex 9, F-38042, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>INSERM, U1216, Université Grenoble Alpes, Grenoble Institut des Neurosciences, BP 170, Grenoble Cedex 9, F-38042</wicri:regionArea><wicri:noRegion>38042</wicri:noRegion><orgName type="university">Université Grenoble-Alpes</orgName><placeName><settlement type="city">Grenoble</settlement><region type="region" nuts="2">Auvergne-Rhône-Alpes</region><region type="old region" nuts="2">Rhône-Alpes</region></placeName></affiliation></author><author><name sortKey="Lesne, Sylvain E" sort="Lesne, Sylvain E" uniqKey="Lesne S" first="Sylvain E" last="Lesné">Sylvain E. Lesné</name><affiliation wicri:level="2"><nlm:affiliation>Department of Neuroscience, University of Minnesota, Minneapolis, MN 55414, USA. lesne002@umn.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neuroscience, University of Minnesota, Minneapolis, MN 55414</wicri:regionArea><placeName><region type="state">Minnesota</region></placeName></affiliation></author></analytic><series><title level="j">Science signaling</title><idno type="eISSN">1937-9145</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Oligomeric forms of amyloid-forming proteins are believed to be the principal initiating bioactive species in many neurodegenerative disorders, including Alzheimer's disease (AD). Amyloid-β (Aβ) oligomers are implicated in AD-associated phosphorylation and aggregation of the microtubule-associated protein tau. To investigate the specific molecular pathways activated by different assemblies, we isolated various forms of Aβ from Tg2576 mice, which are a model for AD. We found that Aβ*56, a 56-kDa oligomer that is detected before patients develop overt signs of AD, induced specific changes in neuronal signaling. In primary cortical neurons, Aβ*56 interacted with N-methyl-d-aspartate receptors (NMDARs), increased NMDAR-dependent Ca(2+) influx, and consequently increased intracellular calcium concentrations and the activation of Ca(2+)-dependent calmodulin kinase IIα (CaMKIIα). In cultured neurons and in the brains of Tg2576 mice, activated CaMKIIα was associated with increased site-specific phosphorylation and missorting of tau, both of which are associated with AD pathology. In contrast, exposure of cultured primary cortical neurons to other oligomeric Aβ forms (dimers and trimers) did not trigger these effects. Our results indicate that distinct Aβ assemblies activate neuronal signaling pathways in a selective manner and that dissecting the molecular events caused by each oligomer may inform more effective therapeutic strategies.</div></front></TEI><affiliations><list><country><li>Australie</li><li>France</li><li>États-Unis</li></country><region><li>Auvergne-Rhône-Alpes</li><li>Minnesota</li><li>Nouvelle-Galles du Sud</li><li>Rhône-Alpes</li></region><settlement><li>Grenoble</li><li>Sydney</li></settlement><orgName><li>Université Grenoble-Alpes</li><li>Université de Sydney</li></orgName></list><tree><country name="États-Unis"><region name="Minnesota"><name sortKey="Amar, Fatou" sort="Amar, Fatou" uniqKey="Amar F" first="Fatou" last="Amar">Fatou Amar</name></region><name sortKey="Boyle, Gabriel" sort="Boyle, Gabriel" uniqKey="Boyle G" first="Gabriel" last="Boyle">Gabriel Boyle</name><name sortKey="Larson, Megan" sort="Larson, Megan" uniqKey="Larson M" first="Megan" last="Larson">Megan Larson</name><name sortKey="Lesne, Sylvain E" sort="Lesne, Sylvain E" uniqKey="Lesne S" first="Sylvain E" last="Lesné">Sylvain E. Lesné</name><name sortKey="Sherman, Mathew A" sort="Sherman, Mathew A" uniqKey="Sherman M" first="Mathew A" last="Sherman">Mathew A. Sherman</name></country><country name="France"><region name="Auvergne-Rhône-Alpes"><name sortKey="Rush, Travis" sort="Rush, Travis" uniqKey="Rush T" first="Travis" last="Rush">Travis Rush</name></region><name sortKey="Buisson, Alain" sort="Buisson, Alain" uniqKey="Buisson A" first="Alain" last="Buisson">Alain Buisson</name></country><country name="Australie"><region name="Nouvelle-Galles du Sud"><name sortKey="Chang, Liu" sort="Chang, Liu" uniqKey="Chang L" first="Liu" last="Chang">Liu Chang</name></region><name sortKey="Gotz, Jurgen" sort="Gotz, Jurgen" uniqKey="Gotz J" first="Jürgen" last="Götz">Jürgen Götz</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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