Suchergebnisse

Down syndrome (DS), caused by trisomy of chromosome 21, is the most common genetic cause of intellectual disability. We recently discovered that green tea extracts containing epigallocatechin-3-gallate (EGCG) improve cognition in mice transgenic for Dyrk1a (TgDyrk1A) and in a trisomic DS mouse model (Ts65Dn). Interestingly, paired with cognitive stimulation, green tea has beneficial pro-cognitive effects in DS individuals. Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase 1A (DYRK1A) is a major candidate to explain the cognitive phenotypes of DS, and inhibiting its activity is a promising pro-cognitive therapy. DYRK1A kinase activity can be normalized in the hippocampus of transgenic DYRK1A mice administering green tea extracts, but also submitting the animals to environmental enrichment (EE). However, many other mechanisms could also explain the pro-cognitive effects of green tea extracts and EE. To underpin the overall alterations arising upon DYRK1A overexpression and the molecular processes underneath the pro-cognitive effects, we used quantitative proteomics. We investigated the hippocampal (phospho)proteome in basal conditions and after treatment with a green tea extract containing EGCG and/or EE in TgDyrk1A and control mice. We found that Dyrk1A overexpression alters protein and phosphoprotein levels of key postsynaptic and plasticity-related pathways and that these alterations were rescued upon the cognitive enhancer treatments. ; The work has received financial support from MINECO (SAF2016-79956-R), Jerome Lejeune Foundation (Project #1347 "Elucidation of the mechanism of action of epigallocatechin-3-gallate as a therapeutic agent on the cognitive phenotype in Down Syndrome mice models"), and the NIH 1R01EB 028159-01 to MD, the Centre for Genomic Regulation Severo Ochoa excellence grant (SEV-2012-0208), the Centro de Investigación Biomédica en Red Enfermedades Raras (CIBER) of Rare Diseases; "Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement de la Generalitat de Catalunya" (Grups consolidats SGR 2016/1125, and 2017SGR595); and the "Centro para el Desarrollo Tecnológico Industrial CDTI." The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech) and it is a member of Proteored, PRB3, and is supported by grant PT17/0019, of the PE I+D+i 2013–2016, funded by ISCIII. ID received funding from the People Program (Marie Curie Actions) of the European Union's Seventh Framework Program (FP7/2007-2013) under REA grant agreement n° 608959. MO received an FPI Severo Ochoa Doctoral Fellowship from the Spanish Ministry of Economy and Finance (MINECO) SVP-2013-068022 during the period 2014–2018 and a short research international stay fellowship (EEBB-I-16-11305).