Prenatal treatment with EGCG enriched green tea extract rescues GAD67 related developmental and cognitive defects in Down syndrome mouse models

Abstract

Down syndrome is a common genetic disorder caused by trisomy of chromosome 21. Brain development in affected foetuses might be improved through prenatal treatment. One potential target is DYRK1A, a multifunctional kinase encoded by chromosome 21 that, when overexpressed, alters neuronal excitation–inhibition balance and increases GAD67 interneuron density. We used a green tea extract enriched in EGCG to inhibit DYRK1A function only during gestation of transgenic mice overexpressing Dyrk1a (mBACtgDyrk1a). Adult mice treated prenatally displayed reduced levels of inhibitory markers, restored VGAT1/VGLUT1 balance, and rescued density of GAD67 interneurons. Similar results for gabaergic and glutamatergic markers and interneuron density were obtained in Dp(16)1Yey mice, trisomic for 140 chromosome 21 orthologs; thus, prenatal EGCG exhibits efficacy in a more complex DS model. Finally, cognitive and behaviour testing showed that adult Dp(16)1Yey mice treated prenatally had improved novel object recognition memory but do not show improvement with Y maze paradigm. These findings provide empirical support for a prenatal intervention that targets specific neural circuitries.

Molecular Rescue of Dyrk1A Overexpression Alterations in Mice with Fontup® Dietary Supplement: Role of Green Tea Catechins

“…Previous studies have shown that EGCG can cross the BBB, even at a very low concentration, by the use of a BBB model kit and in conscious and freely moving rat [34][35][36]. In WT mice the presence of catechins from Mega Green Tea Extract was first assessed in plasma [15]. In our study, EGCG is well detected not only in plasma but also in brain of WT and TgBACDyrk1A mice.…”

“…Many studies aimed at deciphering whether it is possible to correct phenotype through modulation of DYRK1A activity. Preclinical studies performed in mouse models of DS have reported improved behavioral outcomes with EGCG, an inhibitor of DYRK1A [6][7][8][9][10][11][12][13][14][15]. Two clinical trials in adult patients with DS have evaluated the safety and efficacy to improve cognitive phenotypes of green tea extracts containing 45% EGCG [8,16].…”

“…Among them, the green tea catechin, epigallocatechin-3-gallate (EGCG) is the most used in preclinical studies, considering the safety of the molecule and the interesting potency to inhibit DYRK1A activity with IC50 of 330 nM [5]. Most of the DYRK1A inhibition studies with EGCG treatment showed some beneficial effects [6][7][8][9][10][11][12][13][14][15].…”

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

“…Other biomarkers such as DYRK1A act as general inhibitors of neural plasticity. 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 – 168 ). Recent studies have demonstrated that some DYRK1A inhibitors such as the antioxidant Epigallocatechin gallate (EGCG) improve long-term outcomes related with memory and executive function in individuals with Down syndrome ( 166 – 168 ).…”

“…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 – 168 ). Recent studies have demonstrated that some DYRK1A inhibitors such as the antioxidant Epigallocatechin gallate (EGCG) improve long-term outcomes related with memory and executive function in individuals with Down syndrome ( 166 – 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 ).…”