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

Molecular nutrition & food research (2013-09-17)
Rafael De la Torre, Susana De Sola, Meritxell Pons, Arnaud Duchon, María Martínez de Lagran, Magí Farré, Montserrat Fitó, Bessy Benejam, Klaus Langohr, Joan Rodriguez, Mitona Pujadas, Jean Charles Bizot, Aída Cuenca, Nathalie Janel, Silvina Catuara, Maria Isabel Covas, Henri Blehaut, Yann Herault, Jean Marie Delabar, Mara Dierssen
ABSTRACT

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. 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. We conclude that EGCG is a promising therapeutic tool for cognitive enhancement in DS, and its efficacy may depend of Dyrk1A inhibition.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
(−)-Epigallocatechin gallate, ≥95%
Sigma-Aldrich
(−)-Epigallocatechin gallate, ≥80% (HPLC), from green tea
Supelco
Epigallocatechin gallate, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
(−)-Epigallocatechin gallate, analytical standard
Epigallocatechin gallate, primary reference standard