3xTg-AD mice exhibit an activated central stress axis during early-stage pathology - PubMed (original) (raw)

3xTg-AD mice exhibit an activated central stress axis during early-stage pathology

Elaine K Hebda-Bauer et al. J Alzheimers Dis. 2013.

Abstract

Activation of the hypothalamic-pituitary-adrenal (HPA) axis occurs in response to the organism's innate need for homeostasis. The glucocorticoids (GCs) that are released into the circulation upon acute activation of the HPA axis perform stress-adaptive functions and provide negative feedback to turn off the HPA axis, but can be detrimental when in excess. Long-term activation of the HPA axis (such as with chronic stress) enhances susceptibility to neuronal dysfunction and death, and increases vulnerability to Alzheimer's disease (AD). However, little is known how components of the HPA axis, upstream of GCs, impact vulnerability to AD. This study examined basal gene expression of stress-related molecules in brains of 3xTg-AD mice during early-stage pathology. Basal GC levels and mRNA expression of the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and corticotropic releasing hormone (CRH) in several stress- and emotionality-related brain regions were measured in 3-4-month-old 3xTg-AD mice. Despite normal GC levels, young 3xTg-AD mice exhibit an activated central HPA axis, with altered mRNA levels of MR and GR in the hippocampus, GR and CRH in the paraventricular nucleus of the hypothalamus, GR and CRH in the central nucleus of the amygdala, and CRH in the bed nucleus of the stria terminalis. This HPA axis activation is present during early-stage neuropathology when 3xTg-AD mice show mild behavioral changes, suggesting an ongoing neuroendocrine regulation that precedes the onset of severe AD-like pathology and behavioral deficits.

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Figures

Figure 1

EPM and open field behavior in six-month-old WT and 3xTg-AD mice. (A) Nearly half the males and more than half the females of both genotypes never entered the open arms of the EPM or they froze when they did enter an open arm (WT mice only; see checkered areas). (B and C) The distance traveled (B) and the total number of entries (C) in the EPM did not differ between 3xTg-AD and WT mice. (D) The distance traveled in the open field was also similar for 3xTg-AD and WT mice. (E) Male 3xTg-AD mice took significantly longer to enter the periphery after initial placement in the center than WT mice. (F and G) Male and female 3xTg-AD mice spent more time in the center of the open field (F) and exhibited a slower speed of movement (G) during the early part of the test (but they did not freeze—see Latency to Move in Table 1). Data represent mean ± SEM. **&**p<0.05 vs. WT mice, *p<0.05: female 3xTg-AD vs. female WT; **+**p=0.01: male 3xTg-AD vs. male WT; ^p<0.05: female 3xTg-AD vs. male 3xTg-AD; #p<0.05: male 3xTg-AD vs. female WT.

Figure 2

Basal Gene Expression in the hippocampus (HPC) of 3–4-month-old WT and 3xTg-AD mice. (A and B) Representative MR in situ hybridization autoradiographs from male WT (A) and 3xTg-AD (B) mice. (C) Male 3xTg-AD mice show higher MR mRNA expression in the CA3 area of the HPC compared to male WT mice and all female mice. (D and E) Representative GR in situ hybridization autoradiographs of the HPC from male WT (D) and 3xTg-AD (E) mice. (F and G) Male 3xTg-AD mice exhibit higher GR mRNA expression in the CA3 area (F) and dentate gyrus (G) of the HPC compared to male WT mice and female and male WT mice, respectively. Data represent mean ± SEM. *p<0.05; **p<0.01.

Figure 3

Basal Gene Expression in the paraventricular nucleus of the hypothalamus (PVN) of 3–4-month-old WT and 3xTg-AD mice. (A and B) Representative GR in situ hybridization autoradiographs of the PVN from male WT (A) and 3xTg-AD (B) mice. (C and D) Representative CRH in situ hybridization autoradiographs of the PVN from male WT (C) and 3xTg-AD (D) mice. (E) Male 3xTg-AD mice show higher GR mRNA expression in the PVN than male WT mice. (F) Male 3xTg-AD mice exhibit lower CRH mRNA levels in the PVN compared to male WT mice. Data represent mean ± SEM. **p<0.01.

Figure 4

Basal Gene Expression in the central nucleus of the amygdala (CeA) of 3–4-month-old WT and 3xTg-AD mice. (A and B) Representative GR in situ hybridization autoradiographs of the CeA from female (A) and male (B) 3xTg-AD mice. (C and D) Representative CRH in situ hybridization autoradiographs of the CeA from male WT (C) and male 3xTg-AD (D) mice. (E) Female 3xTg-AD mice express higher GR mRNA levels in the CeA than male 3xTg-AD mice and all WT mice. (F) All transgenic mice exhibit higher CRH mRNA expression in the CeA compared to WT mice. Data represent mean ± SEM. ***p<0.001.

Figure 5

Basal CRH Gene Expression in the dorsolateral bed nucleus of the stria terminalis (BSTLD) of 3-4-month-old WT and 3xTg-AD mice. (A and B) Representative CRH in situ hybridization autoradiographs of the BSTLD from male WT (A) and 3xTg-AD (B) mice. Arrows indicate the dorsolateral division of BST. (C) All transgenic mice exhibit higher CRH mRNA expression in the BSTLD compared to WT mice. (D) Schematic of BST nuclei, including the dorsolateral division [44]. Data represent mean ± SEM. *p<0.05; ***p<0.001.

Figure 6

hAβPP/Aβ immunoreactivity in the hippocampus (HPC), posterior parietal association cortex, and posterior basolateral amygdala of 3-month-old male and female 3xTg-AD mice. Representative images of 6E10 immunoreactivity in brain slices at Bregma −2.18 [44] of male (A and C) and female (B and D) 3xTg-AD mice are depicted here. 6E10 immunoreactivity is found in the pyramidal cell layer of the CA1–CA3 areas of the HPC, with little to no staining of fibers in the stratum radiatum or oriens. 6E10 immunoreactivity is also found in Layers IV and V of the cortex and the basolateral amygdala. No 6E10-immunopositive plaques were found. Females exhibit significantly more 6E10 immunoreactivity per area (as measured by percent area sampled) than males in the CA1 area of the HPC and the basolateral amygdala, but not the posterior parietal association cortex. ***p<0.001.

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3xTg-AD mice exhibit an activated central stress axis during early-stage pathology - PubMed (original) (raw)