Epigallocatechin-3-gallate improves cardiac hypertrophy and short-term memory deficits in a Williams-Beuren syndrome mouse model

Abstract

Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder caused by a heterozygous deletion of 26–28 genes at chromosome band 7q11.23. The complete deletion (CD) mouse model mimics the most common deletion found in WBS patients and recapitulates most neurologic features of the disorder along with some cardiovascular manifestations leading to significant cardiac hypertrophy with increased cardiomyocytes’ size. Epigallocatechin-3-gallate (EGCG), the most abundant catechin found in green tea, has been associated with potential health benefits, both on cognition and cardiovascular phenotypes, through several mechanisms. We aimed to investigate the effects of green tea extracts on WBS-related phenotypes through a phase I clinical trial in mice. After feeding CD animals with green tea extracts dissolved in the drinking water, starting at three different time periods (prenatal, youth and adulthood), a set of behavioral tests and several anatomical, histological and molecular analyses were performed. Treatment resulted to be effective in the reduction of cardiac hypertrophy and was also able to ameliorate short-term memory deficits of CD mice. Taken together, these results suggest that EGCG might have a therapeutic and/or preventive role in the management of WBS.

Gtf2i and Gtf2ird1 mutation are not sufficient to reproduce mouse phenotypes caused by the Williams Syndrome critical region

“…In this study, we have replicated several of the phenotypes previously seen in the CD animals, such as marble burying and balance deficits (28, 47, 50). It was shown that CD animals bury fewer marbles than WT animals and rescuing the Gtf2i levels in the hippocampus did not rescue this phenotype.…”

“…We specifically focused on the hippocampus, since we saw deficits in marble burying and differences in contextual fear memory, two behaviors thought to be mediated by hippocampal function (49, 51). Other studies in the CD animals have also shown there to be differences in LTP in the hippocampus as well as differences in Bdnf levels (47, 50). Yet the transcriptional consequences genome-wide of WSCR loss hav not been characterized in the hippocampus.…”

“…This gene was also upregulated in WS iPSCs (24). We also looked at genes that have been investigated previously in the CD mouse, such as Bdnf and Pi3kr (46, 47) and we show that there was little change in gene expression between genotypes (Supplemental Figure 5B).…”

“…This task also requires motor skills and has been used as a proxy for repetitive behaviors (45), which are seen in individuals with WS. It has been previously shown that CD animals bury fewer marbles than WT littermates (46, 47). Here we similarly show that there was significant effect of genotype in this task (F 2,66 =15.243, p=3.61×10 −6 ).…”

“…The three-chamber social approach assay has come under recent criticism due to how dependent it is on activity levels of mice and its lower heritability compared to tests of direct social interaction (53). The CD animals had not previously been tested in this procedure excatly, but have been tested in a modified social approach where the time spent investigating a mouse in a cup is measured but with no competing non-social stimulus (28, 46, 47). The data showed that the CD animals investigated the social stimulus for more time than the WT animals and delivery of Gtf2i cDNA by AAV9 via the magna cisterna can return the investigation time to normal levels (46).…”