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

Han, Bing; Wang, Jinhua; Geng, Yichao; Shen, Li; Wang, Hua-Long; Wang, Yanyong; Wang, Mingwei

doi:10.1159/000471869

Cited by 40 publications

(29 citation statements)

References 49 publications

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“…We observe that that the dysfunction in KEGG pathways related to the metabolism of phospholipid and galactose in functional predictions via Tax4Fun is consistent with the findings of a previous study showing that metabolic mechanisms of stress-related cognitive impairments in APP/PS1 mice were partly related to sphingolipid metabolism [35]. Abnormal phospholipid metabolism is closely related to oxidative stress and inflammatory responses and plays a significant role in the occurrence and development of cardiovascular and cerebrovascular diseases [36].…”

Section: Discussionsupporting

confidence: 89%

Noise exposure-induced intestinal flora dysbiosis disrupts homeostasis of oxi-inflamm-barrier in the gut–brain axis of APP/PS1 mice: implications for early onset Alzheimer's disease

Cui¹,

Chi²,

Cao³

et al. 2020

Preprint

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Background: Environmental noise exposure and genetic risk factors are thought to be associated with gut microbiome that exacerbates Alzheimer’s disease (AD) pathology. However, the role and mechanism of environmental risk factors in early-onset AD (EOAD) pathogenesis remain unclear. Methods: We established APP/PS1 Tg and C57BL/6 (wild type [WT]) mouse models to evaluate the molecular pathways underlying EOAD pathophysiology following environmental noise exposure. 16S rRNA sequencing analyses were used for intestinal flora measurements and Tax4Fun were used to predict the metagenome content from 16S rRNA sequencing results; and assessment of the flora dysbiosis-triggered dyshomeostasis of oxi-inflamm-barrier and the effects of the CNS end of the gut–brain axis were conducted to explore the underlying pathological mechanisms. Results: Both WT and APP/PS1 mice showed statistically significant relationship between environmental noise and the taxonomic composition of the corresponding gut microbiome. Bacterial-encoded functional categories in noise-exposed WT and APP/PS1 mice included phospholipid and galactose metabolism, oxidative stress, and cell senescence. These alterations corresponded with imbalanced intestinal oxidation and anti-oxidation systems and low-grade systemic inflammation after noise exposure. Mechanistically, axis-series experiments demonstrated that after noise exposure, intestinal and hippocampal tight junction proteins levels reduced, whereas serum levels of inflammatory mediator were elevated. With regard to APP/PS1 overexpression, noise-induced abnormalities in the gut–brain axis may contribute to aggravation of neuropathology in the presymptomatic stage of EOAD mice model. Conclusions: Our results demonstrate that noise exposure has deleterious effects on the homeostasis of oxi-inflamm-barrier in the microbiome–gut–brain axis. Therefore, at least in a genetic context, chronic noise may aggravate the progression of EOAD.

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Section: Discussionsupporting

confidence: 89%

Noise exposure-induced intestinal flora dysbiosis disrupts homeostasis of oxi-inflamm-barrier in the gut–brain axis of APP/PS1 mice: implications for early onset Alzheimer's disease

Cui¹,

Chi²,

Cao³

et al. 2020

Preprint

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“…Traditional maze-based tasks often rely on stressful situations to motivate behavior. Stress is known to drive AD progression in humans and animals models (reviewed in Justice, 2018 ) and can decrease cognitive performance in both WT (reviewed in Moreira et al, 2016 ) and APP/PS1 mice ( Han et al, 2016 , 2017 ); an interaction between AD pathology, stress and phenotype is likely. Studies in support of a stress interaction include reports of extinction impairments in APP/PS1 mice, which were only reported in aversive extinction paradigms ( Ramírez-Lugo et al, 2009 ; Bonardi et al, 2011 ; Cheng et al, 2019 ), but not appetitive extinction paradigms ( Bonardi et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

A Preclinical Model of Computerized Cognitive Training: Touchscreen Cognitive Testing Enhances Cognition and Hippocampal Cellular Plasticity in Wildtype and Alzheimer’s Disease Mice

Shepherd

Zhang

Hoffmann

et al. 2021

Front. Behav. Neurosci.

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With the growing popularity of touchscreen cognitive testing in rodents, it is imperative to understand the fundamental effects exposure to this paradigm can have on the animals involved. In this study, we set out to assess hippocampal-dependant learning in the APP/PS1 mouse model of Alzheimer’s disease (AD) on two highly translatable touchscreen tasks – the Paired Associate Learning (PAL) task and the Trial Unique Non-Matching to Location (TUNL) task. Both of these tests are based on human tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and are sensitive to deficits in both mild cognitive impairment (MCI) and AD. Mice were assessed for deficits in PAL at 9–12 months of age, then on TUNL at 8–11 and 13–16 months. No cognitive deficits were evident in APP/PS1 mice at any age, contrary to previous reports using maze-based learning and memory tasks. We hypothesized that daily and long-term touchscreen training may have inadvertently acted as a cognitive enhancer. When touchscreen-tested mice were assessed on the Morris water maze, they showed improved task acquisition compared to naïve APP/PS1 mice and wild-type (WT) littermate controls. In addition, we show that touchscreen-trained WT and APP/PS1 mice show increased cell proliferation and immature neuron numbers in the dentate gyrus compared to behaviorally naïve WT and APP/PS1 mice. This result indicates that the touchscreen testing paradigm could improve cognitive performance, and/or mask an impairment, in experimental mouse models. This touchscreen-induced cognitive enhancement may involve increased neurogenesis, and possibly other forms of cellular plasticity. This is the first study to show increased numbers of proliferating cells and immature neurons in the hippocampus following touchscreen testing, and that touchscreen training can improve cognitive performance in maze-based spatial navigation tasks. This potential for touchscreen testing to induce cognitive enhancement, or other phenotypic shifts, in preclinical models should be considered in study design. Furthermore, touchscreen-mediated cognitive enhancement could have therapeutic implications for cognitive disorders.

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“…Short term “modern life”-like stress ( Baglietto-Vargas et al, 2015 ), chronic isolation stress ( Dong et al, 2004 ), chronic mild/variable stress ( Cuadrado-Tejedor et al, 2012 ), chronic mild social stress ( Rothman et al, 2012 ), chronic restraint/immobilization stress ( Jeong et al, 2006 ; Devi et al, 2010 ), and early life stress ( Sierksma et al, 2012 ; Lesuis et al, 2016 ; Hoeijmakers et al, 2017 ; Hui et al, 2017 ) have all been shown to increase amyloid plaque burden. Stress also accelerates loss in cognitive performance in AD model animals ( Dong et al, 2004 ; Jeong et al, 2006 ; Han et al, 2016 , 2017 ). Stress-induced physiological changes can persist for the life of the animal, as stress exposure in young animals causes elevated CSF Aβ levels for up to 12 months and increases plaque formation, a process which begins months to years after the stress was applied ( Justice et al, 2015 ; Lesuis et al, 2016 ; Hoeijmakers et al, 2017 ).…”

Section: Alzheimer's Disease Pathogenesis Is Exacerbated By Stress Inmentioning

confidence: 99%

The relationship between stress and Alzheimer's disease

Justice

2018

Neurobiology of Stress

172

119

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Stress is critically involved in the development and progression of disease. From the stress of undergoing treatments to facing your own mortality, the physiological processes that stress drives have a serious detrimental effect on the ability to heal, cope and maintain a positive quality of life. This is becoming increasingly clear in the case of neurodegenerative diseases. Neurodegenerative diseases involve the devastating loss of cognitive and motor function which is stressful in itself, but can also disrupt neural circuits that mediate stress responses. Disrupting these circuits produces aberrant emotional and aggressive behavior that causes long-term care to be especially difficult. In addition, added stress drives progression of the disease and can exacerbate symptoms. In this review, I describe how neural and endocrine pathways activated by stress interact with ongoing neurodegenerative disease from both a clinical and experimental perspective.

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

Cited by 40 publications

References 49 publications

Noise exposure-induced intestinal flora dysbiosis disrupts homeostasis of oxi-inflamm-barrier in the gut–brain axis of APP/PS1 mice: implications for early onset Alzheimer's disease

Noise exposure-induced intestinal flora dysbiosis disrupts homeostasis of oxi-inflamm-barrier in the gut–brain axis of APP/PS1 mice: implications for early onset Alzheimer's disease

A Preclinical Model of Computerized Cognitive Training: Touchscreen Cognitive Testing Enhances Cognition and Hippocampal Cellular Plasticity in Wildtype and Alzheimer’s Disease Mice

The relationship between stress and Alzheimer's disease

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