Abstract
Down syndrome (DS) is the main genetic cause of intellectual disability due to triplication of human chromosome 21 (HSA21). Although there is no treatment for intellectual disability, environmental enrichment (EE) and the administration of green tea extracts containing epigallocatechin-3-gallate (EGCG) improve cognition in mouse models and individuals with DS. Using proteome, and phosphoproteome analysis in the hippocampi of a DS mouse model (Ts65Dn), we investigated the possible mechanisms underlying the effects of green tea extracts, EE and their combination. Our results revealed disturbances in cognitive-related (synaptic proteins, neuronal projection, neuron development, microtubule), GTPase/kinase activity and chromatin proteins. Green tea extracts, EE, and their combination restored more than 70% of the phosphoprotein deregulation in Ts65Dn, and induced possible compensatory effects. Our downstream analyses indicate that re-establishment of a proper epigenetic state and rescue of the kinome deregulation may contribute to the cognitive rescue induced by green tea extracts.
Highlights
Down syndrome (DS) is the main genetic cause of intellectual disability due to triplication of human chromosome 21 (HSA21)
Using quantitative mass spectrometry-based proteomics (LC–MS/MS) on whole proteome extracts from Ts65Dn and WT mice, treated or not with EGCG containing green tea extracts (“green tea”), EE, or green tea extracts + EE (n total = 40 mice), we identified 2633 proteins, and 4705 phosphopeptides belonging to 1759 phosphorylated proteins
We found a significant increase in the abundance of 48 proteins, 20 of which were low or absent in WT hippocampi, and significantly decreased abundance of 67 proteins (Fig. 1A,B, Table 1)
Summary
Down syndrome (DS) is the main genetic cause of intellectual disability due to triplication of human chromosome 21 (HSA21). There is no treatment for intellectual disability, environmental enrichment (EE) and the administration of green tea extracts containing epigallocatechin-3gallate (EGCG) improve cognition in mouse models and individuals with DS. Phosphoproteome analysis in the hippocampi of a DS mouse model (Ts65Dn), we investigated the possible mechanisms underlying the effects of green tea extracts, EE and their combination. EE, and their combination restored more than 70% of the phosphoprotein deregulation in Ts65Dn, and induced possible compensatory effects. Recent evidence has shown that green tea extracts containing epigallocatechin-3-gallate (EGCG), a green tea flavonol, improve the cognitive phenotype in trisomic Ts65Dn mice, as well as in individuals with DS1,2, providing a unique opportunity to study the molecular mechanisms underlying its beneficial effects. In Ts65Dn mice, EE improved spatial learning and m emory[8 ], visual f unction[9], normalized brain inhibition, enhanced hippocampal synaptic plasticity, increased branching in pyramidal cells[10] and rescued postnatal neurogenesis d efect[11]
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