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

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

Research output: Contribution to journalArticleResearchpeer-review

158 Citations (Scopus)

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. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Original languageEnglish
Pages (from-to)278-288
JournalMolecular Nutrition and Food Research
Volume58
DOIs
Publication statusPublished - 1 Feb 2014

Keywords

  • Cognition
  • DYRK1A
  • Down syndrome
  • Epigallocatechin gallate
  • Homocysteine

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