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DC Field | Value | Language |
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dc.contributor.author | Jayaraman, Anusha | en_US |
dc.contributor.author | Htike, Thein Than | en_US |
dc.contributor.author | James, Rachel | en_US |
dc.contributor.author | Picon, Carmen | en_US |
dc.contributor.author | Reynolds, Richard | en_US |
dc.date.accessioned | 2021-12-29T07:00:19Z | - |
dc.date.available | 2021-12-29T07:00:19Z | - |
dc.date.issued | 2021 | - |
dc.identifier.citation | Jayaraman, A., Htike, T. T., James, R., Picon, C. & Reynolds, R. (2021). TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampus. Acta Neuropathologica Communications, 9(1), 159-. https://dx.doi.org/10.1186/s40478-021-01264-w | en_US |
dc.identifier.issn | 2051-5960 | en_US |
dc.identifier.uri | https://hdl.handle.net/10356/153812 | - |
dc.description.abstract | 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. | en_US |
dc.description.sponsorship | Nanyang Technological University | en_US |
dc.language.iso | en | en_US |
dc.relation.ispartof | Acta Neuropathologica Communications | en_US |
dc.rights | © 2021 The Author(s). This 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/. The Creative Commons Public Domain Dedication waiver (http://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. | en_US |
dc.subject | Science::Medicine | en_US |
dc.title | TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampus | en_US |
dc.type | Journal Article | en |
dc.contributor.school | Lee Kong Chian School of Medicine (LKCMedicine) | en_US |
dc.contributor.research | Centre for Molecular Neuropathology | en_US |
dc.identifier.doi | 10.1186/s40478-021-01264-w | - |
dc.description.version | Published version | en_US |
dc.identifier.pmid | 34625123 | - |
dc.identifier.scopus | 2-s2.0-85116728690 | - |
dc.identifier.issue | 1 | en_US |
dc.identifier.volume | 9 | en_US |
dc.identifier.spage | 159 | en_US |
dc.subject.keywords | Necroptosis | en_US |
dc.subject.keywords | Alzheimer’s Disease | en_US |
dc.description.acknowledgement | We thank the UK Multiple Sclerosis and Parkinson’s Tissue Bank at Imperial College London (funding from the MS Society of Great Britain, Grant 007/14 to RR) and South West Dementia Brain Bank, University of Bristol, for the supply of post-mortem AD and control brain tissue samples. We thank Anselm Vincent and Dr Brian Z Wang for their assistance with technical support. This work was supported by a LKCMedicine Strategic Academic Initiative award to RR. | en_US |
item.fulltext | With Fulltext | - |
item.grantfulltext | open | - |
Appears in Collections: | LKCMedicine Journal Articles |
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File | Description | Size | Format | |
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s40478-021-01264-w.pdf | 6.04 MB | Adobe PDF | View/Open |
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