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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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Company of Biologists Ltd
2018
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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. |
format | Online Article Text |
id | pubmed-6176987 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | The Company of Biologists Ltd |
record_format | MEDLINE/PubMed |
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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