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

Ilario De Toma,Patrick Aloy,Eduard Sabidó,Mara Dierssen,Mireia Ortega

doi:10.3389/fnmol.2019.00272

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.

Highlights

Down syndrome (DS), caused by trisomy of chromosome 21, is the most common genetic cause of intellectual disability
Setting a threshold of adjusted p-value and fold change of p < 0.05, and | log2(fold change) (log2FC)| > 0.3, we found that Dyrk1A overexpression in transgenic mice overexpressing Dyrk1A (TG) hippocampus resulted in significant changes in the abundance of 98 proteins (51 upregulated and 47 downregulated) compared to WT
Once we had defined the phosphoproteome alterations driven by Dyrk1a overexpression in TG hippocampus, we studied the effects of three pro-cognitive therapies in TG and WT mice on object recognition memory in order to ensure that possibleproteomic changes reflect a procognitive effects in a hippocampal-dependent memory task: (i) green tea extract, which we previously reported to rescue cognitive impairments in the novel object recognition (NOR) task in transgenic Dyrk1A mice (TG) (Martinez de Lagran et al, 2012); (ii) EE, which we previously showed to enhance cognition and reduce Dyrk1a expression (Pons-Espinal et al, 2013); and (iii) the combined treatment with green tea and EE (Figure 3A)

Summary

Introduction

Down syndrome (DS), caused by trisomy of chromosome 21, is the most common genetic cause of intellectual disability. This excessive DYRK1A kinase activity contributes to the DS cognitive disturbances (Altafaj et al, 2001), the motor alterations (Martinez de Lagran et al, 2004), and the characteristic facial features (McElyea et al, 2016), and is associated with the early onset of Alzheimer’s disease (Sheppard et al, 2012) Supporting these findings, transgenic mice overexpressing Dyrk1A (TG) exhibit defects in neurogenesis, reduced dendritic length and branching, and impaired long-term potentiation (LTP) and long-term depression (LTD), and normalization of its expression levels corrects the cognitive impairments seen in trisomic DS mouse models and in DS individuals (De la Torre et al, 2014). EE normalizes DYRK1A kinase activity in the hippocampus and rescues neurogenesis alterations and cognitive impairments in TG mice (Pons-Espinal et al, 2013)

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