Chronic Stress Aggravates Cognitive Impairment and Suppresses Insulin Associated Signaling Pathway in APP/PS1 Mice

Han, Bing; Yu, Lulu; Geng, Yichao; Shen, Li; Wang, Hualong; Wang, Yanyong; Wang, Jinhua; Wang, Mingwei

doi:10.3233/jad-160189

Cited by 48 publications

(34 citation statements)

References 52 publications

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“…Chronic stress not only impaired the early long- term potentiation (LTP) in the at-risk rat model of AD [9], but it also decreased hippocampal synaptic plasticity [10] and increased amyloid-β plaque deposition in Tg2576 mice [11]. Furthermore, our previous study also confirmed that chronic stress exposure increased the levels of glucocorticoids (1.5-fold), promoted senile plaque deposition, neuronal injury, and cognitive impairment in APP/PS1 mice compared to wild-type mice [12]; however, the cognition-related metabolic mechanisms during chronic stress are not well understood.…”

Section: Introductionsupporting

confidence: 58%

“…There is evidence that stress or excessive glucocorticoids, once beyond the tolerable limit, have deleterious effects on brain structure and function; more severe damage may occur in some vulnerable groups, e.g., AD patients[11, 12, 43]. However, few studies have focused on the metabolic pattern in AD during chronic stress.…”

Section: Discussionmentioning

confidence: 99%

“…As it contains some of the highest glucocorticoid receptor levels in the brain, the hippocampus is particularly sensitive to stress [27, 28]. Recently, we found that although the basal levels of corticosterone were similar between C57 and APP/PS1 mice, the stress tolerance of APP/PS1 mice was lower than age-matched C57 mice, as evidenced by dramatically increased corticosterone levels and reduced glucocorticoid receptor (GR) expression in hippocampus following exposure to stress [12]. Similarly, this result showed that CUMS exposure obviously disturbed the metabolic pattern of hippocampal neurons in APP/PS1 mice, while no significant effects were observed in C57 mice, further illustrating an impaired tolerance to stress in APP/PS1 mice.…”

Section: Discussionmentioning

confidence: 99%

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Chronic Stress Contributes to Cognitive Dysfunction and Hippocampal Metabolic Abnormalities in APP/PS1 Mice

Han

Wang

Geng³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Stress response is determined by the brain, and the brain is a sensitive target for stress. Our previous experiments have confirmed that once the stress response is beyond the tolerable limit of the brain, particularly that of the hippocampus, it will have deleterious effects on hippocampal structure and function; however, the metabolic mechanisms for this are not well understood. Methods: Here, we used morris water maze, elisa and gas chromatography-time of flight/mass spectrometry to observe the changes in cognition, neuropathology and metabolomics in the hippocampus of APP/PS1 mice and wild-type (C57) mice caused by chronic unpredictable mild stress (CUMS), we also further explored the correlation between cognition and metabolomics. Results: We found that 4 weeks of CUMS aggravated cognitive impairment and increased amyloid-β deposition in APP/PS1 mice, but did not affect C57 mice. Under non-stress conditions, compared with C57 mice, there were 8 different metabolites in APP/PS1 mice. However, following CUMS, 3 different metabolites were changed compared with untreated C57 mice. Compared to APP/PS1 mice, there were 7 different metabolites in APP/PS1+CUMS mice. Among these alterations, 3-hydroxybutyric acid, valine, serine, beta-alanine and o-phosphorylethanolamine, which are involved in sphingolipid metabolism, synthesis and degradation of ketone bodies, and amino acid metabolism. Conclusion: The results indicate that APP/PS1 mice are more vulnerable to stress than C57 mice, and the metabolic mechanisms of stress-related cognitive impairment in APP/PS1 mice are related to multiple pathways and networks, including sphingolipid metabolism, synthesis and degradation of ketone bodies, and amino acid metabolism.

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Section: Introductionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Chronic Stress Contributes to Cognitive Dysfunction and Hippocampal Metabolic Abnormalities in APP/PS1 Mice

Han

Wang

Geng³

et al. 2017

Cell Physiol Biochem

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“…These unexpected results suggest that the availability of adiponectin receptors can be stabilized even in cases where genetic and environmental risk factors for AD co-occur. Recently, Han et al (2016) demonstrated that insulin receptor levels are decreased in the hippocampus of AD mice and can further decline after stress exposure, concluding that people with harmful genetic mutations are more likely to be vulnerable to stress. Further investigation is necessary to explore the mechanism to explain the difference between the stress-induced changes of adiponectin and insulin receptors.…”

Section: Discussionmentioning

confidence: 99%

Adiponectin Receptors Are Less Sensitive to Stress in a Transgenic Mouse Model of Alzheimer's Disease

et al. 2017

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Background: Adiponectin and leptin are implicated in the initiation and pathomechanism of Alzheimer's disease (AD). The serum concentrations of these adipokines has been extensively studied in AD, however little is known about their receptors in this disease.Objective: We developed a novel approach to examine whether the receptors of adiponectin (AdipoR1 and -R2) and/or leptin (LepR) can contribute to AD pathomechanism. To achieve this, we investigated the effect of both genetic and environmental factors associated with AD on the expression of these receptors.Method: We used C57BL/6J (WT) and APP(swe)/Presen(e9d)1 (AD) mice. Both strains were exposed to restraint stress (RS) daily for 6h over different time periods. Then, we measured the mRNA expression of AdipoR1, AdipoR2 and LepR and the level of AdipoR1 and AdipoR2 proteins in the hippocampal and prefrontal cortical areas of each mouse.Results: We detected brain region specific transcriptomic changes of adiponectin receptors induced by APP and PS1 transgenes. Both acute and chronic RS caused significant elevations in AdipoR1 mRNA expression in the hippocampus of WT mice. In the prefrontal cortex, the mRNA expression of AdipoR1 followed a biphasic course. In AD mice, RS did not promote any changes in the expression of AdipoR1 mRNA and AdipoR1 protein levels. AdipoR2 mRNA in AD animals, however, showed a significant increase in the prefrontal cortex during RS. Regarding AdipoR1 and AdipoR2 mRNA and protein expression, relevant changes could be measured during stress exposure in both brain areas. Furthermore, stress exposed groups exhibited little change in LepR mRNA expression.Conclusion: Our findings indicate that carrying the transgenes associated with AD induces modification in the expression of both adiponectin receptors. In the case of a normal genetic background, these receptors also appear to be sensitive to environmental factors, while in a genetically determined AD model less response to stress stimuli could be observed. The results suggest that modification of adipokine receptors could also be considered in the therapeutic approach to AD.

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“…Repeated stress has been implicated in the pathogenesis of diverse diseases, which ranges from anxiety, depression, posttraumatic stress disorder, and cognitive dysfunction (Henn and Vollmayr, ; Cordner and Tamashiro, ; Han et al, ; Yu et al, ). Several studies have reported that chronic stress impairs spatial learning and memory (McEwen, ; Srikumar et al, ; Ramkumar et al, ; Veena et al, ; Cordner and Tamashiro, ; Han et al, ; Yu et al, ). Indeed, repeated stress results in morphological, cellular, and electrophysiological changes in the hippocampus.…”

mentioning

confidence: 99%

Short‐term exposure to enriched environment rescues chronic stress‐induced impaired hippocampal synaptic plasticity, anxiety, and memory deficits

Bhagya

Srikumar

Veena

et al. 2016

J of Neuroscience Research

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Exposure to prolonged stress results in structural and functional alterations in the hippocampus including reduced long-term potentiation (LTP), neurogenesis, spatial learning and working memory impairments, and enhanced anxiety-like behavior. On the other hand, enriched environment (EE) has beneficial effects on hippocampal structure and function, such as improved memory, increased hippocampal neurogenesis, and progressive synaptic plasticity. It is unclear whether exposure to short-term EE for 10 days can overcome restraint stress-induced cognitive deficits and impaired hippocampal plasticity. Consequently, the present study explored the beneficial effects of short-term EE on chronic stress-induced impaired LTP, working memory, and anxiety-like behavior. Male Wistar rats were subjected to chronic restraint stress (6 hr/day) over a period of 21 days, and then they were exposed to EE (6 hr/day) for 10 days. Restraint stress reduced hippocampal CA1-LTP, increased anxiety-like symptoms in elevated plus maze, and impaired working memory in T-maze task. Remarkably, EE facilitated hippocampal LTP, improved working memory performance, and completely overcame the effect of chronic stress on anxiety behavior. In conclusion, exposure to EE can bring out positive effects on synaptic plasticity in the hippocampus and thereby elicit its beneficial effects on cognitive functions. © 2016 Wiley Periodicals, Inc.

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Chronic Stress Aggravates Cognitive Impairment and Suppresses Insulin Associated Signaling Pathway in APP/PS1 Mice

Cited by 48 publications

References 52 publications

Chronic Stress Contributes to Cognitive Dysfunction and Hippocampal Metabolic Abnormalities in APP/PS1 Mice

Chronic Stress Contributes to Cognitive Dysfunction and Hippocampal Metabolic Abnormalities in APP/PS1 Mice

Adiponectin Receptors Are Less Sensitive to Stress in a Transgenic Mouse Model of Alzheimer's Disease

Short‐term exposure to enriched environment rescues chronic stress‐induced impaired hippocampal synaptic plasticity, anxiety, and memory deficits

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