The University of Southampton
University of Southampton Institutional Repository
Warning ePrints Soton is experiencing an issue with some file downloads not being available. We are working hard to fix this. Please bear with us.

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

Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological inhibitor of DYRK1A
Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological inhibitor of DYRK1A
Growing evidence support 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 remodeling of core brain areas involved in learning/memory processes. The impact of Dyrk1a trisomy and L41 treatment on brain phosphoproteins was investigated by a phosphoproteomics approach, revealing the implication of synaptic (synapsin I) 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.
1754-8403
Nguyen, Thu Lan
52413520-170c-4525-8a5e-925d4bb7195c
Duchon, Arnaud
64a72bbf-045a-4439-996e-23a130e4d3db
Manousopoulou, Antigoni
9a5e4e75-cea9-4d0b-91c8-0fa2af02632f
Loaec, Nadage
92758e10-d1e0-4342-ab86-73b2d023b59d
Villiers, Benoit
bd2d3421-dadf-4bed-b1c3-b8c3998dd958
Pani, Guillaume
4a1c8b47-9c5d-4733-92d8-f5e9dca00cc7
Karatas, Meltem
e8f41e3b-e9c2-4f6d-9d56-281ab295cca0
Mechling, Anna E.
fcc1c02e-0170-4f27-a4a5-cdbd841c5055
Harsan, Laura-Adela
2d6ba89d-7c0e-4c3d-9c6e-01bd8a578157
Limanton, Emmanuelle
5315c0a1-0959-40a3-ba2e-6fed01335585
Bazureau, Jean-Pierre
102fb03b-5b6c-47a3-aaef-767c3ebdac78
Carreaux, Francois
1846cc3d-1d58-4947-943b-e992efae9bc1
Garbis, Spiros
7067fd19-50c9-4d42-9611-f370289470bd
Maijer, Laurent
8ed72802-a65a-47cf-bb60-7e99d153b69f
Herault, Yan
900bab9a-ae22-4bf4-a055-b2c82ef978d7
Nguyen, Thu Lan
52413520-170c-4525-8a5e-925d4bb7195c
Duchon, Arnaud
64a72bbf-045a-4439-996e-23a130e4d3db
Manousopoulou, Antigoni
9a5e4e75-cea9-4d0b-91c8-0fa2af02632f
Loaec, Nadage
92758e10-d1e0-4342-ab86-73b2d023b59d
Villiers, Benoit
bd2d3421-dadf-4bed-b1c3-b8c3998dd958
Pani, Guillaume
4a1c8b47-9c5d-4733-92d8-f5e9dca00cc7
Karatas, Meltem
e8f41e3b-e9c2-4f6d-9d56-281ab295cca0
Mechling, Anna E.
fcc1c02e-0170-4f27-a4a5-cdbd841c5055
Harsan, Laura-Adela
2d6ba89d-7c0e-4c3d-9c6e-01bd8a578157
Limanton, Emmanuelle
5315c0a1-0959-40a3-ba2e-6fed01335585
Bazureau, Jean-Pierre
102fb03b-5b6c-47a3-aaef-767c3ebdac78
Carreaux, Francois
1846cc3d-1d58-4947-943b-e992efae9bc1
Garbis, Spiros
7067fd19-50c9-4d42-9611-f370289470bd
Maijer, Laurent
8ed72802-a65a-47cf-bb60-7e99d153b69f
Herault, Yan
900bab9a-ae22-4bf4-a055-b2c82ef978d7

Nguyen, Thu Lan, Duchon, Arnaud, Manousopoulou, Antigoni, Loaec, Nadage, Villiers, Benoit, Pani, Guillaume, Karatas, Meltem, Mechling, Anna E., Harsan, Laura-Adela, Limanton, Emmanuelle, Bazureau, Jean-Pierre, Carreaux, Francois, Garbis, Spiros, Maijer, Laurent and Herault, Yan (2018) Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological inhibitor of DYRK1A. Disease Models and Mechanisms. (doi:10.1242/dmm.035634).

Record type: Article

Abstract

Growing evidence support 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 remodeling of core brain areas involved in learning/memory processes. The impact of Dyrk1a trisomy and L41 treatment on brain phosphoproteins was investigated by a phosphoproteomics approach, revealing the implication of synaptic (synapsin I) 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.

Text
Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological inhibitor of DYRK1A_dmm_2018 - Accepted Manuscript
Available under License Creative Commons Attribution.
Download (2MB)

More information

Accepted/In Press date: 1 August 2018
e-pub ahead of print date: 16 August 2018
Published date: 27 September 2018

Identifiers

Local EPrints ID: 424563
URI: http://eprints.soton.ac.uk/id/eprint/424563
ISSN: 1754-8403
PURE UUID: 64024da6-eb42-45e7-b577-0cca6d082406
ORCID for Spiros Garbis: ORCID iD orcid.org/0000-0002-1050-0805

Catalogue record

Date deposited: 05 Oct 2018 11:38
Last modified: 26 Nov 2021 02:56

Export record

Altmetrics

Contributors

Author: Thu Lan Nguyen
Author: Arnaud Duchon
Author: Antigoni Manousopoulou
Author: Nadage Loaec
Author: Benoit Villiers
Author: Guillaume Pani
Author: Meltem Karatas
Author: Anna E. Mechling
Author: Laura-Adela Harsan
Author: Emmanuelle Limanton
Author: Jean-Pierre Bazureau
Author: Francois Carreaux
Author: Spiros Garbis ORCID iD
Author: Laurent Maijer
Author: Yan Herault

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×