Epigallocatechin-3-gallate, a DYRK1A inhibitor, rescues cognitive deficits in Down syndrome mouse models and in humans.

Abstract

SCOPE Trisomy for human chromosome 21 results in Down syndrome (DS), which is among the most complex genetic perturbations leading to intellectual disability. Accumulating data suggest that overexpression of the dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), is a critical pathogenic mechanisms in the intellectual deficit. METHODS AND RESULTS Here we show that the green tea flavonol epigallocatechin-gallate (EGCG), a DYRK1A inhibitor, rescues the cognitive deficits of both segmental trisomy 16 (Ts65Dn) and transgenic mice overexpressing Dyrk1A in a trisomic or disomic genetic background, respectively. It also significantly reverses cognitive deficits in a pilot study in DS individuals with effects on memory recognition, working memory and quality of life. We used the mouse models to ensure that EGCG was able to reduce DYRK1A kinase activity in the hippocampus and found that it also induced significant changes in plasma homocysteine levels, which were correlated with Dyrk1A expression levels. Thus, we could use plasma homocysteine levels as an efficacy biomarker in our human study. CONCLUSION We conclude that EGCG is a promising therapeutic tool for cognitive enhancement in DS, and its efficacy may depend of Dyrk1A inhibition.

DOI: 10.1002/mnfr.201300325
0501001502014201520162017
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@article{Torre2014Epigallocatechin3gallateAD, title={Epigallocatechin-3-gallate, a DYRK1A inhibitor, rescues cognitive deficits in Down syndrome mouse models and in humans.}, author={Rafael de la Torre and Susana de Sola and Meritxell Pons and Arnaud Duchon and Mar{\'i}a Mart{\'i}nez de Lagr{\'a}n and Magi Farre and Montserrat Fito and Bessy Benejam and Klaus Langohr and Joan Pau Rodr{\'i}guez and Mitona Pujadas and Jean Charles Bizot and A{\'i}da Cuenca and Nathalie Janel and Silvina Catuara and Maria-Isabel Covas and Henri Bl{\'e}haut and Yann H{\'e}rault and Jean Marie Delabar and Mara Dierssen}, journal={Molecular nutrition & food research}, year={2014}, volume={58 2}, pages={278-88} }