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Published September 27, 2018 | Supplemental Material + Published
Journal Article Open

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

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.

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.).

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Additional details

Created:
August 19, 2023
Modified:
October 18, 2023