Principal Component Analysis of the Effects of Environmental Enrichment and (-)-epigallocatechin-3-gallate on Age-Associated Learning Deficits in a Mouse Model of Down Syndrome.

Mara Dierssen,Ionas Erb,Cedric Notredame,Juan R Gonzalez,Jose Espinosa-Carrasco,Klaus Langohr,Silvina Catuara-Solarz

doi:10.3389/fnbeh.2015.00330

Abstract

Down syndrome (DS) individuals present increased risk for Alzheimer's disease (AD) neuropathology and AD-type dementia. Here, we investigated the use of green tea extracts containing (-)-epigallocatechin-3-gallate (EGCG), as co-adjuvant to enhance the effects of environmental enrichment (EE) in Ts65Dn mice, a segmental trisomy model of DS that partially mimics DS/AD pathology, at the age of initiation of cognitive decline. Classical repeated measures ANOVA showed that combined EE-EGCG treatment was more efficient than EE or EGCG alone to improve specific spatial learning related variables. Using principal component analysis (PCA) we found that several spatial learning parameters contributed similarly to a first PC and explained a large proportion of the variance among groups, thus representing a composite learning measure. This PC1 revealed that EGCG or EE alone had no significant effect. However, combined EE-EGCG significantly ameliorated learning alterations of middle age Ts65Dn mice. Interestingly, PCA revealed an increased variability along learning sessions with good and poor learners in Ts65Dn, and this stratification did not disappear upon treatments. Our results suggest that combining EE and EGCG represents a viable therapeutic approach for amelioration of age-related cognitive decline in DS, although its efficacy may vary across individuals.

Highlights

Down syndrome (DS) is the most prevalent genetic cause of intellectual disability arising from trisomy of chromosome 21 with an incidence of approximately 1 in 1000 live births worldwide
To evaluate the functional impact of EE, EGCG, and the potential synergistic effects of a combination of EE and EGCG (EE-EGCG) on the ageassociated hippocampal-dependent learning and memory deficits of Ts65Dn mice, we compared the behavioral performance of mice treated with EE, EGCG, or EE-EGCG in the MWM with their untreated controls of both wild type (WT) and Ts65Dn genotypes
Signs of dementia in people with DS are the dysfunction of the frontal lobe and hippocampus, where amyloid first accumulates during the early stages

Summary

Introduction

Down syndrome (DS) is the most prevalent genetic cause of intellectual disability arising from trisomy of chromosome 21 with an incidence of approximately 1 in 1000 live births worldwide. Treatment with (-)-epigallocatechin-3-gallate (EGCG), the most abundant polyphenol found in green tea, has gained attention as it has beneficial effects in AD mouse models possibly contributed by its antioxidant activity, free radical scavenging, iron chelating, anti-inflammatory effects, neuroprotection, and promotion of the non-amyloidogenic pathway of APP through ADAM10 maturation (Obregon et al, 2006; Kalfon et al, 2007; Rezai-Zadeh et al, 2008; Biasibetti et al, 2013; Kim et al, 2014). EGCG ameliorates cognitive deficits in AD and DS mouse models, and in young adults with DS (Lee et al, 2013; De la Torre et al, 2014)

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