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

Authors

  • Rafael De la Torre,

    1. Human Pharmacology and Clinical Neurosciences Research Group-Neurosciences Program, IMIM-Hospital del Mar Research Institute, Barcelona, Spain
    2. Cardiovascular Risk and Nutrition Research Group-Inflammatory and Cardiovascular Disorders Program, IMIM-Hospital del Mar Research Institute, and CIBER of Physiopathology of Obesity and Nutrition (CIBEROBN), Barcelona, Spain
    3. University Pompeu Fabra, CEXS-UPF, Barcelona, Spain
    Search for more papers by this author
  • Susana De Sola,

    1. Human Pharmacology and Clinical Neurosciences Research Group-Neurosciences Program, IMIM-Hospital del Mar Research Institute, Barcelona, Spain
    Search for more papers by this author
  • Meritxell Pons,

    1. University Pompeu Fabra, CEXS-UPF, Barcelona, Spain
    2. Center for Genomic Regulation (CRG), and CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
    Search for more papers by this author
  • Arnaud Duchon,

    1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Translational Medicine and Neuroscience Program, IGBMC, CNRS, INSERM, Université de Strasbourg, UMR7104, UMR964, and Institut Clinique de la Souris, ICS, GIE CERBM, Illkirch, France
    Search for more papers by this author
  • María Martínez de Lagran,

    1. University Pompeu Fabra, CEXS-UPF, Barcelona, Spain
    2. Center for Genomic Regulation (CRG), and CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
    Search for more papers by this author
  • Magí Farré,

    1. Human Pharmacology and Clinical Neurosciences Research Group-Neurosciences Program, IMIM-Hospital del Mar Research Institute, Barcelona, Spain
    2. Universitat Autònoma de Barcelona (UDIMAS-UAB), Barcelona, Spain
    Search for more papers by this author
  • Montserrat Fitó,

    1. Cardiovascular Risk and Nutrition Research Group-Inflammatory and Cardiovascular Disorders Program, IMIM-Hospital del Mar Research Institute, and CIBER of Physiopathology of Obesity and Nutrition (CIBEROBN), Barcelona, Spain
    Search for more papers by this author
  • Bessy Benejam,

    1. Fundació Catalana Síndrome de Down, Barcelona, Spain
    Search for more papers by this author
  • Klaus Langohr,

    1. Human Pharmacology and Clinical Neurosciences Research Group-Neurosciences Program, IMIM-Hospital del Mar Research Institute, Barcelona, Spain
    2. Department of Statistics and Operations Research, Universitat Politècnica de Catalunya, Barcelona, Spain
    Search for more papers by this author
  • Joan Rodriguez,

    1. Human Pharmacology and Clinical Neurosciences Research Group-Neurosciences Program, IMIM-Hospital del Mar Research Institute, Barcelona, Spain
    Search for more papers by this author
  • Mitona Pujadas,

    1. Human Pharmacology and Clinical Neurosciences Research Group-Neurosciences Program, IMIM-Hospital del Mar Research Institute, Barcelona, Spain
    2. Cardiovascular Risk and Nutrition Research Group-Inflammatory and Cardiovascular Disorders Program, IMIM-Hospital del Mar Research Institute, and CIBER of Physiopathology of Obesity and Nutrition (CIBEROBN), Barcelona, Spain
    Search for more papers by this author
  • Jean Charles Bizot,

    1. Key-Obs S.A, Allée du Titane, Orléans, France
    Search for more papers by this author
  • Aída Cuenca,

    1. Human Pharmacology and Clinical Neurosciences Research Group-Neurosciences Program, IMIM-Hospital del Mar Research Institute, Barcelona, Spain
    2. Epidemiology of Drugs of Abuse Research Group-Epidemiology and Public Health Program, IMIM-Hospital del Mar Research Institute, Barcelona, Spain
    Search for more papers by this author
  • Nathalie Janel,

    1. Adaptive Functional Biology, EAC CNRS, University Paris Diderot, Sorbonne Paris Cité, Paris, France
    Search for more papers by this author
  • Silvina Catuara,

    1. Center for Genomic Regulation (CRG), and CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
    Search for more papers by this author
  • Maria Isabel Covas,

    1. Cardiovascular Risk and Nutrition Research Group-Inflammatory and Cardiovascular Disorders Program, IMIM-Hospital del Mar Research Institute, and CIBER of Physiopathology of Obesity and Nutrition (CIBEROBN), Barcelona, Spain
    Search for more papers by this author
  • Henri Blehaut,

    1. Jérôme Lejeune Foundation, Paris, France
    Search for more papers by this author
  • Yann Herault,

    1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Translational Medicine and Neuroscience Program, IGBMC, CNRS, INSERM, Université de Strasbourg, UMR7104, UMR964, and Institut Clinique de la Souris, ICS, GIE CERBM, Illkirch, France
    Search for more papers by this author
  • Jean Marie Delabar,

    1. Epidemiology of Drugs of Abuse Research Group-Epidemiology and Public Health Program, IMIM-Hospital del Mar Research Institute, Barcelona, Spain
    Search for more papers by this author
  • Mara Dierssen

    Corresponding author
    1. University Pompeu Fabra, CEXS-UPF, Barcelona, Spain
    2. Center for Genomic Regulation (CRG), and CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
    • Correspondence: Dr. Mara Dierssen, Systems Biology Program, Genomic Regulation Center (CRG), and CIBER de Enfermedades Raras (CIBERER), Dr Aiguader 88, 08003 Barcelona, Spain

      E-mail: mara.dierssen@crg.es

      Fax: +34-933160099

    Search for more papers by this author

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.

Ancillary