Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/153812
Full metadata record
DC FieldValueLanguage
dc.contributor.authorJayaraman, Anushaen_US
dc.contributor.authorHtike, Thein Thanen_US
dc.contributor.authorJames, Rachelen_US
dc.contributor.authorPicon, Carmenen_US
dc.contributor.authorReynolds, Richarden_US
dc.date.accessioned2021-12-29T07:00:19Z-
dc.date.available2021-12-29T07:00:19Z-
dc.date.issued2021-
dc.identifier.citationJayaraman, 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-wen_US
dc.identifier.issn2051-5960en_US
dc.identifier.urihttps://hdl.handle.net/10356/153812-
dc.description.abstractThe 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.sponsorshipNanyang Technological Universityen_US
dc.language.isoenen_US
dc.relation.ispartofActa Neuropathologica Communicationsen_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.subjectScience::Medicineen_US
dc.titleTNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampusen_US
dc.typeJournal Articleen
dc.contributor.schoolLee Kong Chian School of Medicine (LKCMedicine)en_US
dc.contributor.researchCentre for Molecular Neuropathologyen_US
dc.identifier.doi10.1186/s40478-021-01264-w-
dc.description.versionPublished versionen_US
dc.identifier.pmid34625123-
dc.identifier.scopus2-s2.0-85116728690-
dc.identifier.issue1en_US
dc.identifier.volume9en_US
dc.identifier.spage159en_US
dc.subject.keywordsNecroptosisen_US
dc.subject.keywordsAlzheimer’s Diseaseen_US
dc.description.acknowledgementWe 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.fulltextWith Fulltext-
item.grantfulltextopen-
Appears in Collections:LKCMedicine Journal Articles
Files in This Item:
File Description SizeFormat 
s40478-021-01264-w.pdf6.04 MBAdobe PDFThumbnail
View/Open

SCOPUSTM   
Citations 5

83
Updated on Mar 26, 2024

Web of ScienceTM
Citations 5

63
Updated on Oct 29, 2023

Page view(s)

113
Updated on Mar 29, 2024

Download(s) 50

81
Updated on Mar 29, 2024

Google ScholarTM

Check

Altmetric


Plumx

Items in DR-NTU are protected by copyright, with all rights reserved, unless otherwise indicated.