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TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampus

The pathogenetic mechanisms underlying neuronal death and dysfunction in Alzheimer’s disease (AD) remain unclear. However, chronic neuroinflammation has been implicated in stimulating or exacerbating neuronal damage. The tumor necrosis factor (TNF) superfamily of cytokines are involved in many syste...

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Autores principales: Jayaraman, Anusha, Htike, Thein Than, James, Rachel, Picon, Carmen, Reynolds, Richard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501605/
https://www.ncbi.nlm.nih.gov/pubmed/34625123
http://dx.doi.org/10.1186/s40478-021-01264-w
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author Jayaraman, Anusha
Htike, Thein Than
James, Rachel
Picon, Carmen
Reynolds, Richard
author_facet Jayaraman, Anusha
Htike, Thein Than
James, Rachel
Picon, Carmen
Reynolds, Richard
author_sort Jayaraman, Anusha
collection PubMed
description The pathogenetic mechanisms underlying neuronal death and dysfunction in Alzheimer’s disease (AD) remain unclear. However, chronic neuroinflammation has been implicated in stimulating or exacerbating neuronal damage. The tumor necrosis factor (TNF) superfamily of cytokines are involved in many systemic chronic inflammatory and degenerative conditions and are amongst the key mediators of neuroinflammation. TNF binds to the TNFR1 and TNFR2 receptors to activate diverse cellular responses that can be either neuroprotective or neurodegenerative. In particular, TNF can induce programmed necrosis or necroptosis in an inflammatory environment. Although activation of necroptosis has recently been demonstrated in the AD brain, its significance in AD neuron loss and the role of TNF signaling is unclear. We demonstrate an increase in expression of multiple proteins in the TNF/TNF receptor-1-mediated necroptosis pathway in the AD post-mortem brain, as indicated by the phosphorylation of RIPK3 and MLKL, predominantly observed in the CA1 pyramidal neurons. The density of phosphoRIPK3 + and phosphoMLKL + neurons correlated inversely with total neuron density and showed significant sexual dimorphism within the AD cohort. In addition, apoptotic signaling was not significantly activated in the AD brain compared to the control brain. Exposure of human iPSC-derived glutamatergic neurons to TNF increased necroptotic cell death when apoptosis was inhibited, which was significantly reversed by small molecule inhibitors of RIPK1, RIPK3, and MLKL. In the post-mortem AD brain and in human iPSC neurons, in response to TNF, we show evidence of altered expression of proteins of the ESCRT III complex, which has been recently suggested as an antagonist of necroptosis and a possible mechanism by which cells can survive after necroptosis has been triggered. Taken together, our results suggest that neuronal loss in AD is due to TNF-mediated necroptosis rather than apoptosis, which is amenable to therapeutic intervention at several points in the signaling pathway. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-021-01264-w.
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spelling pubmed-85016052021-10-20 TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampus Jayaraman, Anusha Htike, Thein Than James, Rachel Picon, Carmen Reynolds, Richard Acta Neuropathol Commun Research The pathogenetic mechanisms underlying neuronal death and dysfunction in Alzheimer’s disease (AD) remain unclear. However, chronic neuroinflammation has been implicated in stimulating or exacerbating neuronal damage. The tumor necrosis factor (TNF) superfamily of cytokines are involved in many systemic chronic inflammatory and degenerative conditions and are amongst the key mediators of neuroinflammation. TNF binds to the TNFR1 and TNFR2 receptors to activate diverse cellular responses that can be either neuroprotective or neurodegenerative. In particular, TNF can induce programmed necrosis or necroptosis in an inflammatory environment. Although activation of necroptosis has recently been demonstrated in the AD brain, its significance in AD neuron loss and the role of TNF signaling is unclear. We demonstrate an increase in expression of multiple proteins in the TNF/TNF receptor-1-mediated necroptosis pathway in the AD post-mortem brain, as indicated by the phosphorylation of RIPK3 and MLKL, predominantly observed in the CA1 pyramidal neurons. The density of phosphoRIPK3 + and phosphoMLKL + neurons correlated inversely with total neuron density and showed significant sexual dimorphism within the AD cohort. In addition, apoptotic signaling was not significantly activated in the AD brain compared to the control brain. Exposure of human iPSC-derived glutamatergic neurons to TNF increased necroptotic cell death when apoptosis was inhibited, which was significantly reversed by small molecule inhibitors of RIPK1, RIPK3, and MLKL. In the post-mortem AD brain and in human iPSC neurons, in response to TNF, we show evidence of altered expression of proteins of the ESCRT III complex, which has been recently suggested as an antagonist of necroptosis and a possible mechanism by which cells can survive after necroptosis has been triggered. Taken together, our results suggest that neuronal loss in AD is due to TNF-mediated necroptosis rather than apoptosis, which is amenable to therapeutic intervention at several points in the signaling pathway. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-021-01264-w. BioMed Central 2021-09-28 /pmc/articles/PMC8501605/ /pubmed/34625123 http://dx.doi.org/10.1186/s40478-021-01264-w Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Jayaraman, Anusha
Htike, Thein Than
James, Rachel
Picon, Carmen
Reynolds, Richard
TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampus
title TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampus
title_full TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampus
title_fullStr TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampus
title_full_unstemmed TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampus
title_short TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampus
title_sort tnf-mediated neuroinflammation is linked to neuronal necroptosis in alzheimer's disease hippocampus
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501605/
https://www.ncbi.nlm.nih.gov/pubmed/34625123
http://dx.doi.org/10.1186/s40478-021-01264-w
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