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

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...

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Autores principales: Nguyen, Thu Lan, Duchon, Arnaud, Manousopoulou, Antigoni, Loaëc, Nadège, Villiers, Benoît, Pani, Guillaume, Karatas, Meltem, Mechling, Anna E., Harsan, Laura-Adela, Limanton, Emmanuelle, Bazureau, Jean-Pierre, Carreaux, François, Garbis, Spiros D., Meijer, Laurent, Herault, Yann
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176987/
https://www.ncbi.nlm.nih.gov/pubmed/30115750
http://dx.doi.org/10.1242/dmm.035634
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author Nguyen, Thu Lan
Duchon, Arnaud
Manousopoulou, Antigoni
Loaëc, Nadège
Villiers, Benoît
Pani, Guillaume
Karatas, Meltem
Mechling, Anna E.
Harsan, Laura-Adela
Limanton, Emmanuelle
Bazureau, Jean-Pierre
Carreaux, François
Garbis, Spiros D.
Meijer, Laurent
Herault, Yann
author_facet Nguyen, Thu Lan
Duchon, Arnaud
Manousopoulou, Antigoni
Loaëc, Nadège
Villiers, Benoît
Pani, Guillaume
Karatas, Meltem
Mechling, Anna E.
Harsan, Laura-Adela
Limanton, Emmanuelle
Bazureau, Jean-Pierre
Carreaux, François
Garbis, Spiros D.
Meijer, Laurent
Herault, Yann
author_sort Nguyen, Thu Lan
collection PubMed
description 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.
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spelling pubmed-61769872018-10-16 Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological inhibitor of DYRK1A Nguyen, Thu Lan Duchon, Arnaud Manousopoulou, Antigoni Loaëc, Nadège Villiers, Benoît Pani, Guillaume Karatas, Meltem Mechling, Anna E. Harsan, Laura-Adela Limanton, Emmanuelle Bazureau, Jean-Pierre Carreaux, François Garbis, Spiros D. Meijer, Laurent Herault, Yann Dis Model Mech Research Article 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. The Company of Biologists Ltd 2018-09-01 2018-09-27 /pmc/articles/PMC6176987/ /pubmed/30115750 http://dx.doi.org/10.1242/dmm.035634 Text en © 2018. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0This 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.
spellingShingle Research Article
Nguyen, Thu Lan
Duchon, Arnaud
Manousopoulou, Antigoni
Loaëc, Nadège
Villiers, Benoît
Pani, Guillaume
Karatas, Meltem
Mechling, Anna E.
Harsan, Laura-Adela
Limanton, Emmanuelle
Bazureau, Jean-Pierre
Carreaux, François
Garbis, Spiros D.
Meijer, Laurent
Herault, Yann
Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological inhibitor of DYRK1A
title Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological inhibitor of DYRK1A
title_full Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological inhibitor of DYRK1A
title_fullStr Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological inhibitor of DYRK1A
title_full_unstemmed Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological inhibitor of DYRK1A
title_short Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological inhibitor of DYRK1A
title_sort correction of cognitive deficits in mouse models of down syndrome by a pharmacological inhibitor of dyrk1a
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176987/
https://www.ncbi.nlm.nih.gov/pubmed/30115750
http://dx.doi.org/10.1242/dmm.035634
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