Traumatic stress history interacts with sex and chronic peripheral inflammation to alter mitochondrial function of synaptosomes

Shaw, Gladys A.; Hyer, Molly M.; Targett, Imogen; Dyer, Samya K.; Turkson, Susie; Burns, Chloe M.; Neigh, Gretchen N.

doi:10.1016/j.bbi.2020.05.021

Cited by 17 publications

(6 citation statements)

References 71 publications

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“…We also found mitochondrial alterations in the synaptosomes of ES-exposed WT mice, in line with impairments to respiration in synaptosomal mitochondria found in adult mice exposed to chronic stress, 64 and our previously reported age-associated ES effects on the hippocampal gene expression of the mitochondrial fission protein Fis1, accompanied by hypothalamic and peripheral disruptions to electron transport chain activity. 65 Intriguingly, our data suggest that mitochondria are a shared substrate via which both ES and Aβ pathology induce hippocampal deficits, disturb energy homeostasis, and potentially altered synaptic physiology.…”

Section: Synaptic Mitochondria Are Impacted By Both Es Exposure and T...supporting

confidence: 89%

Early‐life stress and amyloidosis in mice share pathogenic pathways involving synaptic mitochondria and lipid metabolism

Kotah,

Kater,

Brosens

et al. 2023

Alzheimer's & Dementia

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INTRODUCTIONEarly‐life stress (ES) increases the risk for Alzheimer's disease (AD). We and others have shown that ES aggravates amyloid‐beta (Aβ) pathology and promotes cognitive dysfunction in APP/PS1 mice, but underlying mechanisms remain unclear.METHODSWe studied how ES affects the hippocampal synaptic proteome in wild‐type (WT) and APP/PS1 mice at early and late pathological stages, and validated hits using electron microscopy and immunofluorescence.RESULTSThe hippocampal synaptosomes of both ES‐exposed WT and early‐stage APP/PS1 mice showed a relative decrease in actin dynamics‐related proteins and a relative increase in mitochondrial proteins. ES had minimal effects on older WT mice, while strongly affecting the synaptic proteome of advanced stage APP/PS1 mice, particularly the expression of astrocytic and mitochondrial proteins.DISCUSSIONOur data show that ES and amyloidosis share pathogenic pathways involving synaptic mitochondrial dysfunction and lipid metabolism, which may underlie the observed impact of ES on the trajectory of AD.

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Section: Synaptic Mitochondria Are Impacted By Both Es Exposure and T...supporting

confidence: 89%

Early‐life stress and amyloidosis in mice share pathogenic pathways involving synaptic mitochondria and lipid metabolism

Kotah,

Kater,

Brosens

et al. 2023

Alzheimer's & Dementia

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“…This study did not observe the effects of chronic adolescent stress in adulthood, but previous studies have shown that these behavior and immune alterations persist well into adulthood (Shaw et al, 2020), long after conclusion of the stressor exposure. This study has shown that predatory stress only impacts peripheral cytokine levels, however it is possible that these inflammatory alterations within the brain do not appear until much later, in adulthood or within other brain regions.…”

Section: Discussioncontrasting

confidence: 79%

Adolescent predatory stress increases peripheral TNFα response to LPS regardless of sex

Dyer

Shaw

Turkson

et al. 2021

Preprint

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Chronic adolescent stress has been shown to cause increased adverse effects in response to an immune stressor later in life including the development of anxiety and PTSD. Following stress, the production of inflammatory cytokines including IL-1β and TNFα is expected to increase in response to an immune challenge such as LPS. Male and female mice underwent fifteen consecutive days of predatory stress. Chronic adolescent stress was shown to increase both anxiety-like behavior (F(1, 28) = 19.82, p = 0.0001) and TNFα levels within the periphery (F(1, 19) = 4.748, p = 0.0421).

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“…In rodents, female mice show increased ETC activity, ATP production, and fatty acid utilization, whereas mitochondria from male mice show increased ROS production, mitochondrial biogenesis, protein utilization, and Ca 2+ uptake ( Ventura-Clapier et al, 2017 ). In response to chronic peripheral administration of LPS, a recent study found that female, but not male mice developed impaired respiration of synaptosomal mitochondria ( Shaw et al, 2020 ). Also, female mice treated with LPS had fewer mitochondria per pre-synaptic terminal as compared to controls and showed a high incidence of mitochondria with broken membranes and cristae, which were not observed in male mice.…”

Section: Sex Differences In Mitochondria Function In Inflammation-associated Depressionmentioning

confidence: 99%

Neuronal Mitochondrial Dysfunction and Bioenergetic Failure in Inflammation-Associated Depression

2021

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Depression is a leading cause of disability and affects more than 4% of the population worldwide. Even though its pathophysiology remains elusive, it is now well accepted that peripheral inflammation might increase the risk of depressive episodes in a subgroup of patients. However, there is still insufficient knowledge about the mechanisms by which inflammation induces alterations in brain function. In neurodegenerative and neuroinflammatory diseases, extensive studies have reported that inflammation negatively impacts mitochondrial health, contributing to excitotoxicity, oxidative stress, energy deficits, and eventually neuronal death. In addition, damaged mitochondria can release a wide range of damage-associated molecular patterns that are potent activators of the inflammatory response, creating a feed-forward cycle between oxidative stress, mitochondrial impairment, inflammation, and neuronal dysfunction. Surprisingly, the possible involvement of this vicious cycle in the pathophysiology of inflammation-associated depression remains understudied. In this mini-review we summarize the research supporting the association between neuroinflammation, mitochondrial dysfunction, and bioenergetic failure in inflammation-associated depression to highlight the relevance of further studies addressing this crosstalk.

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Traumatic stress history interacts with sex and chronic peripheral inflammation to alter mitochondrial function of synaptosomes

Cited by 17 publications

References 71 publications

Early‐life stress and amyloidosis in mice share pathogenic pathways involving synaptic mitochondria and lipid metabolism

Early‐life stress and amyloidosis in mice share pathogenic pathways involving synaptic mitochondria and lipid metabolism

Adolescent predatory stress increases peripheral TNFα response to LPS regardless of sex

Neuronal Mitochondrial Dysfunction and Bioenergetic Failure in Inflammation-Associated Depression

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