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Chronic stress induces NPD-like behavior in APPPS1 and WT mice with subtle differences in gene expression.

ABSTRACT: Neuropsychiatric disturbances (NPDs) are considered hallmarks of Alzheimer's disease (AD). Nevertheless, treatment of these symptoms has proven difficult and development of safe and effective treatment options is hampered by the limited understanding of the underlying pathophysiology. Thus, robust preclinical models are needed to increase knowledge of NPDs in AD and develop testable hypotheses and novel treatment options. Abnormal activity of the hypothalamic-pituitary-adrenal (HPA) axis is implicated in many psychiatric symptoms and might contribute to both AD and NPDs development and progression. We aimed to establish a mechanistic preclinical model of NPD-like behavior in the APPPS1 mouse model of AD and wildtype (WT) littermates. In APPPS1 and WT mice, we found that chronic stress increased anxiety-like behavior and altered diurnal locomotor activity suggestive of sleep disturbances. Also, chronic stress activated the HPA axis, which, in WT mice, remained heightened for additional 3 weeks. Chronic stress caused irregular expression of circadian regulatory clock genes (BMAL1, PER2, CRY1 and CRY2) in both APPPS1 and WT mice. Interestingly, APPPS1 and WT mice responded differently to chronic stress in terms of expression of serotonergic markers (5-HT_1A receptor and MAOA) and inflammatory genes (IL-6, STAT3 and ADMA17). These findings indicate that, although the behavioral response to chronic stress might be similar, the neurobiochemical response was different in APPPS1 mice, which is an important insight in the efforts to develop safe and effective treatments options for NPDs in AD patients. Further work is needed to substantiate these findings.

SUBMITTER: Clement A

PROVIDER: S-EPMC9285501 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Epidemiologic studies have shown that the prevalence of stress-related mood disorders is higher in women, which suggests a different response of neuroendocrine circuits involved in the response to stressful events, as well as a genetic background influence. The aim of this study was to investigate the baseline differences in anxiety-like behaviors of females of two commonly used mice strains. Secondly, we have also aimed to study their behavioral and biochemical alterations following stress. Naïve 3-4 months-old Swiss and C57BL/6 female mice were evaluated in the elevated plus maze (EPM) and in the acoustic startle response (ASR) for anxiety-like behaviors. Besides, an independent group of animals from each strain was exposed to cold-restraint stress (30?min/4?°C, daily) for 21 consecutive days and then evaluated in EPM and in the sucrose consumption tests. Twenty-four hours following behavioral experimentation mice were decapitated and their hippocampi (HP) and cortex (CT) dissected for further Western blotting analysis of glucocorticoid receptor (GR) and glial fibrillary acid protein (GFAP). Subsequent to each behavioral protocol, animal blood samples were collected for further plasma corticosterone analysis. C57BL/6 presented a lower anxiety profile than Swiss female mice in both behavioral tests, EPM and ASR. These phenomena could be correlated with the fact that both strains have distinct corticosterone levels and GR expression in the HP at the baseline level. Moreover, C57BL/6 female mice were more vulnerable to the stress protocol, which was able to induce an anhedonic state characterized by lower preference for a sucrose solution. Behavioral anhedonic-like alterations in these animals coincide with reduced plasma corticosterone accompanied with increased GR and GFAP levels, both in the HP. Our data suggest that in C57BL/6 female mice a dysregulation of the hypothalamus-pituitary-adrenal axis (HPA-axis) occurs, in which corticosterone acting on GRs would possibly exert its pro-inflammatory role, ultimately leading to astrocyte activation in response to stress.

Project description:Although previous studies have reported that serum folate levels are negatively associated with depression in women but not men, it remains unclear whether folate deficiency can directly lead to depression and whether sex difference serves a role in this condition, since the potential mechanism remains elusive. Therefore, the present study aimed to investigate whether folate deficiency results in differences in parameters associated with depression between males and females. CD-1 mice received either a standard control diet or a folate-deficient diet from 10 to 38 weeks of age, following which behavioral assays, such as an open field test, sucrose preference test and forced swim test were performed throughout week 38. Serum and cerebral cortex samples were subsequently collected for assessment. Serum folate, homocysteine, estradiol (E2) and testosterone levels were measured using chemiluminescence, enzymatic cycling assay and electrochemiluminescence immunoassays. The cerebral cortex was used for western blot analysis, to detect the expression levels of estrogen receptor β (ERβ), PI3K/AKT pathway and caspase-3. The results revealed that compared with those in female mice that received standard control diet, female mice that received folate-deficient diet exhibited lower E2 concentrations, lower sucrose preferences (as determined through the sucrose preference test), longer durations of immobility (as determined in the forced swim test) and less time spent in the central areas of the open field test. Western blotting demonstrated that the expression levels of ERβ and the phosphorylation levels of PI3K and AKT were decreased, whilst the expression levels of cleaved caspase-3 were increased, in the cerebral cortex of female mice that received folate-deficient diet. However, no differences in E2 concentration, behavioral assay parameters or protein levels of ERβ, phosphorylated (p-)PI3K, p-AKT and cleaved caspase-3 could be observed in male mice regardless of whether they received standard control or folate-deficient diets. Collectively, these results revealed that folate deficiency only led to depression-like behavior in female mice. This may be associated with reduced E2 levels, which may inhibit the PI3K/AKT pathway and upregulate the expression of cleaved caspase-3 to promote neuronal apoptosis.

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Chronic stress induces NPD-like behavior in APPPS1 and WT mice with subtle differences in gene expression.

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