Chronic Mild Stress Modified Epigenetic Mechanisms Leading to Accelerated Senescence and Impaired Cognitive Performance in Mice.

Dolors Puigoriol-Illamola,Mirna Martínez-Damas,Mercè Pallàs,Christian Griñán-Ferré

doi:10.3390/ijms21031154

Abstract

Cognitive and behavioural disturbances are a growing public healthcare issue for the modern society, as stressful lifestyle is becoming more and more common. Besides, several pieces of evidence state that environment is crucial in the development of several diseases as well as compromising healthy aging. Therefore, it is important to study the effects of stress on cognition and its relationship with aging. To address these queries, Chronic Mild Stress (CMS) paradigm was used in the senescence-accelerated mouse prone 8 (SAMP8) and resistant 1 (SAMR1). On one hand, we determined the changes produced in the three main epigenetic marks after 4 weeks of CMS treatment, such as a reduction in histone posttranslational modifications and DNA methylation, and up-regulation or down-regulation of several miRNA involved in different cellular processes in mice. In addition, CMS treatment induced reactive oxygen species (ROS) damage accumulation and loss of antioxidant defence mechanisms, as well as inflammatory signalling activation through NF-κB pathway and astrogliosis markers, like Gfap. Remarkably, CMS altered mTORC1 signalling in both strains, decreasing autophagy only in SAMR1 mice. We found a decrease in glycogen synthase kinase 3 β (GSK-3β) inactivation, hyperphosphorylation of Tau and an increase in sAPPβ protein levels in mice under CMS. Moreover, reduction in the non-amyloidogenic secretase ADAM10 protein levels was found in SAMR1 CMS group. Consequently, detrimental effects on behaviour and cognitive performance were detected in CMS treated mice, affecting mainly SAMR1 mice, promoting a turning to SAMP8 phenotype. In conclusion, CMS is a feasible intervention to understand the influence of stress on epigenetic mechanisms underlying cognition and accelerating senescence.

Highlights

Aging is a multifactorial process characterized by a progressive loss of physiological integrity, resulting in an impaired function and increased vulnerability to death
In attempting to systematically address which are the epigenetic modifications caused by chronic mild stressful stimuli, we studied the major epigenetic marks that include histone modifications, DNA methylation and non-coding RNAs
We studied global histone 3 (H3) and histone 4 (H4) acetylation, phosphorylation of histone 2A (H2A.X) protein levels, methylation of H3 acetylated at Lys9 protein levels, as well as several deacetylases gene expression and/or protein levels, such as histone deacetylase 2 (HDAC2), Sirt1, Sirt2, and Sirt6

Summary

Introduction

Aging is a multifactorial process characterized by a progressive loss of physiological integrity, resulting in an impaired function and increased vulnerability to death. Physiological brain aging involves cognitive impairment, which includes decreased learning and memory abilities and slower responses to different stimulus [1]. Environmental factors drive epigenetic modifications, resulting in phenotypic differences, which alter almost all tissues and organs. The brain is one of the most affected structures, such modifications lead to a progressive decline in the cognitive function and create a favourable context for the development of neurodegenerative diseases [2]. Aging is the most significant risk factor for most chronic diseases, such as age-related cognitive decline and Alzheimer’s disease (AD) [3]. AD is the most prevalent dementia and its progression is influenced by both genetic and environmental factors [4]

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