De Toma, IlarioOrtega Crespo, Mireia, 1988-Aloy, Patrick, 1972-Sabidó Aguadé, Eduard, 1981-Dierssen, Mara2020-03-242020-03-242019De Toma I, Ortega M, Aloy P, Sabidó E, Dierssen M. DYRK1A overexpression alters cognition and neural-related proteomic pathways in the hippocampus that are rescued by green tea extract and/or environmental enrichment. Front Mol Neurosci. 2019; 12:272. DOI: 10.3389/fnmol.2019.002721662-5099http://hdl.handle.net/10230/44006Down 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.application/pdfeng© 2019 De Toma, Ortega, Aloy, Sabidó and Dierssen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.info:eu-repo/semantics/articlehttp://dx.doi.org/10.3389/fnmol.2019.00272DYRK1ADown syndromeEGCGEnvironmental enrichmentGreen tea extractHippocampusProteomicsRecognition memoryinfo:eu-repo/semantics/openAccess