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A 3′UTR modification of the TNF-α mouse gene increases peripheral TNF-α and modulates the Alzheimer-like phenotype in 5XFAD mice
Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine, involved in Alzheimer’s disease pathogenesis. Anti-TNF-α therapeutic approaches currently used in autoimmune diseases have been proposed as a therapeutic strategy in AD. We have previously examined the role of TNF-α and anti-TNF-α drugs...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250826/ https://www.ncbi.nlm.nih.gov/pubmed/32457323 http://dx.doi.org/10.1038/s41598-020-65378-2 |
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author | Kalovyrna, Nikoleta Apokotou, Olympia Boulekou, Sotiria Paouri, Evi Boutou, Athena Georgopoulos, Spiros |
author_facet | Kalovyrna, Nikoleta Apokotou, Olympia Boulekou, Sotiria Paouri, Evi Boutou, Athena Georgopoulos, Spiros |
author_sort | Kalovyrna, Nikoleta |
collection | PubMed |
description | Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine, involved in Alzheimer’s disease pathogenesis. Anti-TNF-α therapeutic approaches currently used in autoimmune diseases have been proposed as a therapeutic strategy in AD. We have previously examined the role of TNF-α and anti-TNF-α drugs in AD, using 5XFAD mice, and we have found a significant role for peripheral TNF-α in brain inflammation. Here we investigated the role of mouse TNF-α on the AD-like phenotype of 5XFAD mice using a knock-in mouse with deletion of the 3’UTR of the endogenous TNF-α (TNF(ΔARE/+)) that develops rheumatoid arthritis and Crohn’s disease. 5XFAD/TNF(ΔARE/+) mice showed significantly decreased amyloid deposition. Interestingly, microglia but not astrocytes were activated in 5XFAD/ TNF(ΔARE/+) brains. This microglial activation was associated with increased infiltrating peripheral leukocytes and perivascular macrophages and synaptic degeneration. APP levels and APP processing enzymes involved in Aβ production remained unchanged, suggesting that the reduced amyloid burden can be attributed to the increased microglial and perivascular macrophage activation caused by TNF-α. Peripheral TNF-α levels were increased while brain TNF-α remained the same. These data provide further evidence for peripheral TNF-α as a mediator of inflammation between the periphery and the brain. |
format | Online Article Text |
id | pubmed-7250826 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-72508262020-06-04 A 3′UTR modification of the TNF-α mouse gene increases peripheral TNF-α and modulates the Alzheimer-like phenotype in 5XFAD mice Kalovyrna, Nikoleta Apokotou, Olympia Boulekou, Sotiria Paouri, Evi Boutou, Athena Georgopoulos, Spiros Sci Rep Article Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine, involved in Alzheimer’s disease pathogenesis. Anti-TNF-α therapeutic approaches currently used in autoimmune diseases have been proposed as a therapeutic strategy in AD. We have previously examined the role of TNF-α and anti-TNF-α drugs in AD, using 5XFAD mice, and we have found a significant role for peripheral TNF-α in brain inflammation. Here we investigated the role of mouse TNF-α on the AD-like phenotype of 5XFAD mice using a knock-in mouse with deletion of the 3’UTR of the endogenous TNF-α (TNF(ΔARE/+)) that develops rheumatoid arthritis and Crohn’s disease. 5XFAD/TNF(ΔARE/+) mice showed significantly decreased amyloid deposition. Interestingly, microglia but not astrocytes were activated in 5XFAD/ TNF(ΔARE/+) brains. This microglial activation was associated with increased infiltrating peripheral leukocytes and perivascular macrophages and synaptic degeneration. APP levels and APP processing enzymes involved in Aβ production remained unchanged, suggesting that the reduced amyloid burden can be attributed to the increased microglial and perivascular macrophage activation caused by TNF-α. Peripheral TNF-α levels were increased while brain TNF-α remained the same. These data provide further evidence for peripheral TNF-α as a mediator of inflammation between the periphery and the brain. Nature Publishing Group UK 2020-05-26 /pmc/articles/PMC7250826/ /pubmed/32457323 http://dx.doi.org/10.1038/s41598-020-65378-2 Text en © The Author(s) 2020 Open Access 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Kalovyrna, Nikoleta Apokotou, Olympia Boulekou, Sotiria Paouri, Evi Boutou, Athena Georgopoulos, Spiros A 3′UTR modification of the TNF-α mouse gene increases peripheral TNF-α and modulates the Alzheimer-like phenotype in 5XFAD mice |
title | A 3′UTR modification of the TNF-α mouse gene increases peripheral TNF-α and modulates the Alzheimer-like phenotype in 5XFAD mice |
title_full | A 3′UTR modification of the TNF-α mouse gene increases peripheral TNF-α and modulates the Alzheimer-like phenotype in 5XFAD mice |
title_fullStr | A 3′UTR modification of the TNF-α mouse gene increases peripheral TNF-α and modulates the Alzheimer-like phenotype in 5XFAD mice |
title_full_unstemmed | A 3′UTR modification of the TNF-α mouse gene increases peripheral TNF-α and modulates the Alzheimer-like phenotype in 5XFAD mice |
title_short | A 3′UTR modification of the TNF-α mouse gene increases peripheral TNF-α and modulates the Alzheimer-like phenotype in 5XFAD mice |
title_sort | 3′utr modification of the tnf-α mouse gene increases peripheral tnf-α and modulates the alzheimer-like phenotype in 5xfad mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250826/ https://www.ncbi.nlm.nih.gov/pubmed/32457323 http://dx.doi.org/10.1038/s41598-020-65378-2 |
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