Effects of chronic variable stress on cognition and Bace1 expression among wild-type mice.

Z A Cordner,K L K Tamashiro

doi:10.1038/tp.2016.127

Abstract

Stressful life events, activation of the hypothalamic–pituitary–adrenal (HPA) axis and glucocorticoids are now thought to have a role in the development of several neurodegenerative and psychiatric disorders including Alzheimer’s disease (AD) through mechanisms that may include exacerbation of cognitive impairment, neuronal loss, and beta-amyloid (Aβ) and tau neuropathology. In the current study, we use a wild-type mouse model to demonstrate that chronic variable stress impairs cognitive function and that aged mice are particularly susceptible. We also find that stress exposure is associated with a 1.5- to 2-fold increase in the expression of Bace1 in the hippocampus of young adult mice and the hippocampus, prefrontal cortex and amygdala of aged mice. Further, the increased expression of Bace1 was associated with decreased methylation of several CpGs in the Bace1 promoter region. In a second series of experiments, exposure to environmental enrichment (EE) prevented the stress-related changes in cognition, gene expression and DNA methylation. Together, these findings re-affirm the adverse effects of stress on cognition and further suggest that aged individuals are especially susceptible. In addition, demonstrating that chronic stress results in decreased DNA methylation and increased expression of Bace1 in the brain may provide a novel link between stress, Aβ pathology and AD. Finally, understanding the mechanisms by which EE prevented the effects of stress on cognition and Bace1 expression will be an important area of future study that may provide insights into novel approaches to the treatment of AD.

Highlights

In Alzheimer’s disease (AD), prior studies using transgenic models indicate that stress exposure might exacerbate beta-amyloid (Aβ) and tau neuropathology,[10,11] and it is thought that two genes whose products are centrally involved in Aβ pathology, App and Bace[1], contain response elements bound by glucocorticoid receptors.[10,12]
Prolonged or chronic activation of the hypothalamic–pituitary– adrenal (HPA) axis has been consistently associated with neuronal loss, decreased neurogenesis and altered neural connectivity[5,7,18,19,20,22,23,24,25] and, underlying mechanisms remain less well understood, stress exposure has been strongly linked to alterations in epigenetic markers that may lead to changes in gene expression
In one study, exposure of young adult mice to chronically high levels of CORT resulted in impaired performance in the novel object recognition (NOR) test, Barnes maze and Morris water maze.[54]

Summary

INTRODUCTION

Activation of the hypothalamic–pituitary– adrenal (HPA) axis and glucocorticoids are thought to have a role in the development of several neurodegenerative and psychiatric disorders including Alzheimer’s disease (AD).[1,2,3,4,5,6,7,8,9] In AD, prior studies using transgenic models indicate that stress exposure might exacerbate beta-amyloid (Aβ) and tau neuropathology,[10,11] and it is thought that two genes whose products are centrally involved in Aβ pathology, App and Bace[1], contain response elements bound by glucocorticoid receptors.[10,12] App codes for the amyloid precursor protein (APP) and Bace[1] codes for the beta-secretase enzyme, which cleaves APP in the first step of the pathway leading to Aβ peptides and βamyloid plaques. It is clear that exposure to glucocorticoids can induce epigenetic modifications of the Fkbp[5] gene, which codes for a protein that normally functions as a cochaperone of the glucocorticoid receptor,[26,27] but, in AD, it may facilitate tau aggregation.[28,29,30] In addition, epigenetic modifications have been strongly implicated in the regulation of Bdnf,[31,32,33,34] and decreased expression may be involved in a number of neurodegenerative disorders.[35,36] several studies have found global changes in epigenetic markers in AD,[37,38,39] a recent genome-wide analysis found DNA methylation (DNAm) differences in post-mortem AD brains at a single locus,[40] and a study using transgenic mice indicated that chromatin modification might regulate the expression of Bace1.41. Exploration of an object was defined as being within 2 cm of contact while facing an object

MATERIALS AND METHODS

RESULTS

DISCUSSION

Findings

CONFLICT OF INTEREST