title: Epigallocatechin-3-gallate, a DYRK1A inhibitor, rescues cognitive deficits in Down syndrome mouse models and in humans.
abstract: METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  We conclude that EGCG is a promising therapeutic tool for cognitive enhancement in DS, and its efficacy may depend of Dyrk1A inhibition.
authors.affiliation: Human Pharmacology and Clinical Neurosciences Research Group-Neurosciences Program, IMIM-Hospital del Mar Research Institute, Barcelona, Spain; 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; University Pompeu Fabra, CEXS-UPF, Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: De la Torre
authors.forename: Susana
authors.initials: S
authors.lastname: De Sola
authors.forename: Meritxell
authors.initials: M
authors.lastname: Pons
authors.forename: Arnaud
authors.initials: A
authors.lastname: Duchon
authors.forename: María Martínez
authors.initials: MM
authors.lastname: de Lagran
authors.forename: Magí
authors.initials: M
authors.lastname: Farré
authors.forename: Montserrat
authors.initials: M
authors.lastname: Fitó
authors.forename: Bessy
authors.initials: B
authors.lastname: Benejam
authors.forename: Klaus
authors.initials: K
authors.lastname: Langohr
authors.forename: Joan
authors.initials: J
authors.lastname: Rodriguez
authors.forename: Mitona
authors.initials: M
authors.lastname: Pujadas
authors.forename: Jean Charles
authors.initials: JC
authors.lastname: Bizot
authors.forename: Aída
authors.initials: A
authors.lastname: Cuenca
authors.forename: Nathalie
authors.initials: N
authors.lastname: Janel
authors.forename: Silvina
authors.initials: S
authors.lastname: Catuara
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Covas
authors.forename: Henri
authors.initials: H
authors.lastname: Blehaut
authors.forename: Yann
authors.initials: Y
authors.lastname: Herault
authors.forename: Jean Marie
authors.initials: JM
authors.lastname: Delabar
authors.forename: Mara
authors.initials: M
authors.lastname: Dierssen
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002392:Catechin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D004311:Double-Blind Method; D004314:Down Syndrome / Q000188:drug therapy*; D005260:Female; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009030:Mosaicism; D010766:Phosphorylation; D010865:Pilot Projects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014314:Trisomy / Q000235:genetics; D055815:Young Adult; D000097603:Dyrk Kinases
chemical_list: D015415:Biomarkers; D002392:Catechin; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases; C045651:epigallocatechin gallate
keywords: Cognition; DYRK1A; Down syndrome; Epigallocatechin gallate; Homocysteine