Reactive oxygen species released from astrocytes treated with amyloid beta oligomers elicit neuronal calcium signals that decrease phospho-Ser727-STAT3 nuclear content

Muñoz, Yorka; Paula-Lima, Andrea; Núñez, Marco T.

doi:10.1016/j.freeradbiomed.2018.01.006

Cited by 17 publications

(18 citation statements)

References 74 publications

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“…Accordingly, we found that mixed hippocampal cultures treated with LPS from Aa presented an increase in Aβ 1-42 production (Table 4). Based on these results, we propose that a feed forward injurious cycle would emerge, in which the increase in the levels of pro-inflammatory cytokines would activate amyloidogenic secretases to produce increased Aβ 1-42 levels [44], and the increase in the levels of Aβ 1-42 would activate glial cells to produce proinflammatory cytokines [24].…”

Section: Discussionmentioning

confidence: 96%

“…In the case of Aa, the LPS from serotype b specifically induced release of inflammatory cytokines by microglia and in mixed hippocampal cultures, but only in the last case an important change in neuronal morphology was observed, with a clear and strikingly neuritic beading (Figures 3 and 4). Interestingly, neuritic beading induced by activated microglia is an early feature of neuronal dysfunction, which occurs in response to Aβ-induced inflammatory responses involving astrocytes and microglia [24,42]. In addition, neuroinflammation induced by LPS enhances Aβ generation [43].…”

Section: Discussionmentioning

confidence: 99%

“…Rat cortical microglia were obtained as previously described [24]. Briefly, cerebral cortex from 1-to 3-dayold Sprague-Dawley either male or female rat pups were dissected in Hank's-buffered salt solution and digested using 0.25% trypsin supplemented with 0.5 mg/mL DNase I.…”

Section: Microglial Culturesmentioning

confidence: 99%

“…Although M2 cells can neutralize the presence of these inflammatory mediators, under constant and enhanced cytokine production M2 cells fail to achieve their homeostatic role, leading to M1 cell activation and consequent astrocyte induction [14,23]. These molecular and cellular processes generate a cellular response known as astrogliosis, which leads to oxidative stress, low import of glucose and oxygen, ROS and Aβ production, which affects neuronal physiology [16,23,24]. Thus, virulence factors of pathogenic bacteria are likely to play a role during the etiopathogenesis of neurodegenerative disorders, contributing to M1-phenotype polarization and astrogliosis.…”

Section: Introductionmentioning

confidence: 99%

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Serotype b of Aggregatibacter actinomycetemcomitans triggers pro-inflammatory responses and amyloid beta secretion in hippocampal cells: a novel link between periodontitis and Alzheimer´s disease?

Díaz‐Zúñiga

Muñoz

Melgar‐Rodríguez

et al. 2019

Journal of Oral Microbiology

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Introduction: Previous reports have proposed that Periodontal disease (PDis) predisposes to Alzheimer's disease (AD), both highly prevalent pathologies among the elderly. The bacteria Aggregatibacter actinomycetemcomitans (Aa), associated with the most aggressive forms of PDis, are classified in different serotypes with distinct virulence according to the antigenicity of their lipopolysaccharide (LPS). Methods: Here, we determined the effects of purified LPS, from serotypes a, b or c of Aa, on primary cultures of microglia or mixed hippocampal cells. Results: We found that both culture types exhibited higher levels of inflammatory cytokines (IL-1β, IL-6 and TNFα) when treated with serotype b-LPS, compared with controls, as quantified by qPCR and/or ELISA. Also, cultures treated with serotype a-LPS displayed increased mRNA levels of the modulatory cytokines IL-4 and IL-10. Mixed hippocampal cultures treated with serotype b-LPS exhibited severe neuronal morphological changes and displayed increased levels of secreted Aβ 1-42 peptide. These results indicate that LPS from different Aa serotypes triggers discriminatory immune responses, which differentially affect primary hippocampal cells. Conclusion: Altogether, our results show that treatment with serotype b-LPS triggers the secretion of proinflammatory cytokines by microglia, induces neurite shrinking, and increases the extracellular Aβ1-42 levels, all features strongly associated with the etiology of AD.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Microglial Culturesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Serotype b of Aggregatibacter actinomycetemcomitans triggers pro-inflammatory responses and amyloid beta secretion in hippocampal cells: a novel link between periodontitis and Alzheimer´s disease?

Díaz‐Zúñiga

Muñoz

Melgar‐Rodríguez

et al. 2019

Journal of Oral Microbiology

View full text Add to dashboard Cite

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“…In addition, SCI is followed by an acute but long-lasting inflammatory response, marked by invasion of blood-borne cells and activation of endogenous cells and a significant increase in reactive oxygen species (ROS) generation [6]. ROS accumulation could enhance neuronal apoptosis via protein breakdown, lipid peroxidation and DNA damage [7,8]. Oxidative stress leads to the activation of glial cells and promotes the release of pro-inflammatory factors [9].…”

Section: Introductionmentioning

confidence: 99%

Targeting CARD6 attenuates spinal cord injury (SCI) in mice through inhibiting apoptosis, inflammation and oxidative stress associated ROS production

Wang

Luo

Liu

2019

Aging

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Spinal cord injury (SCI) causes long-term and severe disability, influencing the quality of life and triggering serious socioeconomic consequences. Lack of effective pharmacotherapies for SCI is largely attributable to an incomplete understanding of its pathogenesis. Caspase recruitment domain family member 6 (CARD6) was initially suggested to be a protein playing significant role in NF-κB activation. However, the effects of CARD6 on SCI progression remain unknown. In this study, the wild type (CARD6+/+), CARD6 knockout (CARD6-/-) and CARD6 transgenic (TG) mice were subjected to a SCI model in vivo, and in vitro experiments were conducted by treating microglia cells with lipopolysaccharide (LPS). Here, we identified CARD6 as a suppressor of SCI in mice. CARD6 knockout significantly accelerated functional deficits, neuron death and glia activation, whereas CARD6 overexpression resulted in the opposite effects. Both in vivo and in vitro SCI models suggested that CARD6 knockout markedly promoted apoptosis by increasing Cyto-c release to cytosol from mitochondria and activating Caspase-3 signaling. In addition, CARD6 knockout mice exhibited stronger inflammatory response after SCI, as evidenced by the significantly elevated expression of pro-inflammatory cytokines TNF-α, IL-1β and IL-6, which was largely through enhancing the activation of NF-κB signaling.

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Investigating the role that astrocytes play in mediating changes in synaptic health in Alzheimer’s disease

Johnson

Noble

Perez‐Nievas

2020

Alzheimer's & Dementia

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Background Previous results from our group showed that abeta‐stimulated astrocytes release factors that are detrimental to neurons. Our aim is to investigate and validate those factors. One cytokine in particular is shown to be increased after treatment with low concentrations of oligomeric abeta and has been associated with abnormal tau cleavage. We analysed the effect of the cytokine on neuronal health and complexity and on localisation of tau. We also investigated whether the change in phenotype of astrocytes in response to abeta depends on abeta internalisation, and which pathways are involved. Method Primary astrocytic and neuronal cultures were prepared from CD1 mice following standard protocols. Neurons were treated with the cytokine and/or its receptor antagonist and transfected with GFP to allow measurement of dendritic spine density and neurite complexity. Localisation of tau was examined in similarly treated neurons by immunocytochemistry. To investigate abeta internalisation, transgenic conditioned media containing abeta was collected from Tg2576 neurons, with medium from littermate wild type neurons as a control. Astrocytes were treated with conditioned media in the presence or absence of Dynasore, a small molecule inhibitor of dynamin GTPases, and abeta uptake assessed by immunocytochemistry. Result Exposure of neurons to the cytokine results in a reduction of dendritic spine density and neuronal complexity which is rescued when its receptor is blocked by a specific inhibitor. Exposure to the cytokine also seems to affect tau localisation in neurons, causing mislocalisation of tau from the axonal to the somatodendritic compartment. Preliminary data shows that astrocytes internalise abeta quite quickly following addition to the medium, at least in part through endocytosis. Conclusion The phenotype of astrocytes is altered in response to abeta, causing their secretion of molecules, including cytokines. Exposure of neurons to one of these cytokines causes reduced neuronal health and complexity, further confirming that factors released by astrocytes are synaptotoxic.

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Reactive oxygen species released from astrocytes treated with amyloid beta oligomers elicit neuronal calcium signals that decrease phospho-Ser727-STAT3 nuclear content

Cited by 17 publications

References 74 publications

Serotype b of Aggregatibacter actinomycetemcomitans triggers pro-inflammatory responses and amyloid beta secretion in hippocampal cells: a novel link between periodontitis and Alzheimer´s disease?

Serotype b of Aggregatibacter actinomycetemcomitans triggers pro-inflammatory responses and amyloid beta secretion in hippocampal cells: a novel link between periodontitis and Alzheimer´s disease?

Targeting CARD6 attenuates spinal cord injury (SCI) in mice through inhibiting apoptosis, inflammation and oxidative stress associated ROS production

Investigating the role that astrocytes play in mediating changes in synaptic health in Alzheimer’s disease

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