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Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological inhibitor of DYRK1A

Nguyen, Thu Lan and Duchon, Arnaud and Manousopoulou, Antigoni and Loaëc, Nadège and Villiers, Benoît and Pani, Guillaume and Karatas, Meltem and Mechling, Anna E. and Harsan, Laura-Adela and Limanton, Emmanuelle and Bazureau, Jean-Pierre and Carreaux, François and Garbis, Spiros D. and Meijer, Laurent and Herault, Yann (2018) Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological inhibitor of DYRK1A. Disease Models & Mechanisms, 11 (9). Art. No. dmm035634. ISSN 1754-8403. https://resolver.caltech.edu/CaltechAUTHORS:20181008-145923003

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Abstract

Growing evidence supports the implication of DYRK1A in the development of cognitive deficits seen in Down syndrome (DS) and Alzheimer's disease (AD). We here demonstrate that pharmacological inhibition of brain DYRK1A is able to correct recognition memory deficits in three DS mouse models with increasing genetic complexity [Tg(Dyrk1a), Ts65Dn, Dp1Yey], all expressing an extra copy of Dyrk1a. Overexpressed DYRK1A accumulates in the cytoplasm and at the synapse. Treatment of the three DS models with the pharmacological DYRK1A inhibitor leucettine L41 leads to normalization of DYRK1A activity and corrects the novel object cognitive impairment observed in these models. Brain functional magnetic resonance imaging reveals that this cognitive improvement is paralleled by functional connectivity remodelling of core brain areas involved in learning/memory processes. The impact of Dyrk1a trisomy and L41 treatment on brain phosphoproteins was investigated by a quantitative phosphoproteomics method, revealing the implication of synaptic (synapsin 1) and cytoskeletal components involved in synaptic response and axonal organization. These results encourage the development of DYRK1A inhibitors as drug candidates to treat cognitive deficits associated with DS and AD.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1242/dmm.035634DOIArticle
http://dmm.biologists.org/lookup/doi/10.1242/dmm.035634.supplementalPublisherSupplementary Information
ORCID:
AuthorORCID
Garbis, Spiros D.0000-0002-1050-0805
Meijer, Laurent0000-0003-3511-4916
Herault, Yann0000-0001-7049-6900
Additional Information:© 2018 Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. Received May 11, 2018; Accepted August 1, 2018; Published 27 September 2018. Competing interests: L.M. is founder, CEO and CSO of ManRos Therapeutics, which licensed the patent on leucettines and develops these as DS/AD drug candidates. L.M., F.C. and J.-P.B. are co-inventors on the leucettine patent. Author contributions: Conceptualization: T.L.N., A.D., S.D.G., L.M., Y.H.; Methodology: T.L.N., A.D., N.L., B.V., M.K., A.E.M., L.-A.H., E.L., J.-P.B., F.C., S.D.G.; Software: M.K., A.E.M., L.-A.H., S.D.G.; Validation: T.L.N., B.V., L.M.; Formal analysis: T.L.N., A.M., M.K., A.E.M., L.-A.H., S.D.G.; Investigation: T.L.N., A.D., A.M., N.L., B.V., G.P., M.K., A.E.M., J.-P.B., F.C., S.D.G.; Resources: A.M., E.L., J.-P.B., F.C.; Data curation: A.M., M.K., A.E.M., L.-A.H., S.D.G.; Writing - original draft: T.L.N., L.M.; Writing - review & editing: T.L.N., S.D.G., L.M., Y.H.; Supervision: S.D.G., L.M., Y.H.; Project administration: L.M., Y.H.; Funding acquisition: L.M., Y.H. This work was supported by Fonds Unique Interministériel (TRIAD project; L.M., Y.H., J.-P.B.), Conseil Régional de Bretagne (L.M., Y.H., J.-P.B.), Fondation Jérôme Lejeune (L.M.), Seventh Framework Programme (BlueGenics; L.M.), Agence Nationale de la Recherche (Programme Investissements d'Avenir; ANR-10-IDEX-0002-02, ANR-10-LABX-0030-INRT, ANR-10-INBS-07 PHENOMIN to Y.H.) and CIFRE (T.L.N.).
Funders:
Funding AgencyGrant Number
Fonds Unique InterministérielUNSPECIFIED
Conseil Régional de BretagneUNSPECIFIED
Fondation Jérôme LejeuneUNSPECIFIED
European Research Council (ERC)UNSPECIFIED
Agence Nationale pour la Recherche (ANR)ANR-10-IDEX-0002-02
Agence Nationale pour la Recherche (ANR)ANR-10-LABX-0030-INRT
Agence Nationale pour la Recherche (ANR)ANR-10-INBS-07 PHENOMIN
Convention Industrielle de Formation par la Recherche (CIFRE)UNSPECIFIED
Subject Keywords:DYRK1A, Kinase inhibitor, Leucettine, Down syndrome, Synapsin
Issue or Number:9
Record Number:CaltechAUTHORS:20181008-145923003
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20181008-145923003
Official Citation:Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological inhibitor of DYRK1A Thu Lan Nguyen, Arnaud Duchon, Antigoni Manousopoulou, Nadège Loaëc, Benoît Villiers, Guillaume Pani, Meltem Karatas, Anna E. Mechling, Laura-Adela Harsan, Emmanuelle Limanton, Jean-Pierre Bazureau, François Carreaux, Spiros D. Garbis, Laurent Meijer, Yann Herault Disease Models & Mechanisms 2018 11: dmm035634 doi: 10.1242/dmm.035634 Published 27 September 2018
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:90163
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:08 Oct 2018 22:20
Last Modified:03 Oct 2019 20:22

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