DYRK1A Overexpression Alters Cognition and Neural-Related Proteomic Pathways in the Hippocampus That Are Rescued by Green Tea Extract and/or Environmental Enrichment

Abstract

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.

Re-establishment of the epigenetic state and rescue of kinome deregulation in Ts65Dn mice upon treatment with green tea extract and environmental enrichment

“…Our pro-cognitive treatment had a different effect on wild type mice than in Ts65Dn mice, confirming our previous observations in DYRK1A transgenic mice 7 . Around 44% of the proteins changing upon pro-cognitive treatments were common in wild type and trisomic mice, but with an opposite direction of change (Fig.…”

“…The pro-cognitive potential of green tea extracts and environmental enrichment was already shown in previous works 1,2,5,7,12,13 , but the molecular effect on the proteome and phosphoproteome remained elusive. We here show that these pro-cognitive treatments are able to restore more than 70% of the protein deregulation in trisomic mice, and induce compensatory mechanisms by acting on proteins of the same categories.…”

“…Previous studies had shown that both green tea extract with EGCG and environmental enrichment inhibit the tyrosine kinase DYRK1A 5 , which regulates the phosphorylation of many important proteins in the brain 2,22 . In a previous study 7 , we showed that both treatments could similarly rescue 70% of the Dyrk1A transgenic hippocampal (phospho-)protein network. Interestingly, 26 DYRK1A targets were seed proteins of the Ts65Dn network and more than 65% of these proteins were rescued by one of the pro-cognitive treatments.…”

“…However our previous study showed that, the combined treatment with EE and Green tea extracts improved corticohippocampal-dependent learning in both young and middle age Ts65Dn mice 12,13 . Conversely in DYRK1A transgenic mice the combined treatment did not show better results compared to EGCG alone 7 .…”

Murine Models for the Study of Fetal Alcohol Spectrum Disorders: An Overview

“…Its over-expression in different brain areas due to environmental insults or stress conditions reduces neural plasticity in neurons promoting cognitive problems and intellectual disability (166)(167)(168). Recent studies have demonstrated that some DYRK1A inhibitors such as the antioxidant Epigallocatechin gallate (EGCG) improve longterm outcomes related with memory and executive function in individuals with Down syndrome (166)(167)(168). Although it is currently under study, the inhibition of DYRK1A could improve the cognitive performance in pathologies associated to the loss of neuronal functions and plasticity, e.g., FASD, Autism, or Down Syndrome (169).…”