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Alterations in iron content, iron-regulatory proteins and behaviour without tau pathology at one year following repetitive mild traumatic brain injury

Repetitive mild traumatic brain injury (r-mTBI) has increasingly become recognised as a risk factor for the development of neurodegenerative diseases, many of which are characterised by tau pathology, metal dyshomeostasis and behavioural impairments. We aimed to characterise the status of tau and th...

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Autores principales: Juan, Sydney M. A., Daglas, Maria, Truong, Phan H., Mawal, Celeste, Adlard, Paul A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10353227/
https://www.ncbi.nlm.nih.gov/pubmed/37464280
http://dx.doi.org/10.1186/s40478-023-01603-z
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author Juan, Sydney M. A.
Daglas, Maria
Truong, Phan H.
Mawal, Celeste
Adlard, Paul A.
author_facet Juan, Sydney M. A.
Daglas, Maria
Truong, Phan H.
Mawal, Celeste
Adlard, Paul A.
author_sort Juan, Sydney M. A.
collection PubMed
description Repetitive mild traumatic brain injury (r-mTBI) has increasingly become recognised as a risk factor for the development of neurodegenerative diseases, many of which are characterised by tau pathology, metal dyshomeostasis and behavioural impairments. We aimed to characterise the status of tau and the involvement of iron dyshomeostasis in repetitive controlled cortical impact injury (5 impacts, 48 h apart) in 3-month-old C57Bl6 mice at the chronic (12-month) time point. We performed a battery of behavioural tests, characterised the status of neurodegeneration-associated proteins (tau and tau-regulatory proteins, amyloid precursor protein and iron-regulatory proteins) via western blot; and metal levels using bulk inductively coupled plasma-mass spectrometry (ICP-MS). We report significant changes in various ipsilateral iron-regulatory proteins following five but not a single injury, and significant increases in contralateral iron, zinc and copper levels following five impacts. There was no evidence of tau pathology or changes in tau-regulatory proteins following five impacts, although some changes were observed following a single injury. Five impacts resulted in significant gait deficits, mild anhedonia and mild cognitive deficits at 9–12 months post-injury, effects not seen following a single injury. To the best of our knowledge, we are the first to describe chronic changes in metals and iron-regulatory proteins in a mouse model of r-mTBI, providing a strong indication towards an overall increase in brain iron levels (and other metals) in the chronic phase following r-mTBI. These results bring to question the relevance of tau and highlight the involvement of iron dysregulation in the development and/or progression of neurodegeneration following injury, which may lead to new therapeutic approaches in the future. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-023-01603-z.
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spelling pubmed-103532272023-07-19 Alterations in iron content, iron-regulatory proteins and behaviour without tau pathology at one year following repetitive mild traumatic brain injury Juan, Sydney M. A. Daglas, Maria Truong, Phan H. Mawal, Celeste Adlard, Paul A. Acta Neuropathol Commun Research Repetitive mild traumatic brain injury (r-mTBI) has increasingly become recognised as a risk factor for the development of neurodegenerative diseases, many of which are characterised by tau pathology, metal dyshomeostasis and behavioural impairments. We aimed to characterise the status of tau and the involvement of iron dyshomeostasis in repetitive controlled cortical impact injury (5 impacts, 48 h apart) in 3-month-old C57Bl6 mice at the chronic (12-month) time point. We performed a battery of behavioural tests, characterised the status of neurodegeneration-associated proteins (tau and tau-regulatory proteins, amyloid precursor protein and iron-regulatory proteins) via western blot; and metal levels using bulk inductively coupled plasma-mass spectrometry (ICP-MS). We report significant changes in various ipsilateral iron-regulatory proteins following five but not a single injury, and significant increases in contralateral iron, zinc and copper levels following five impacts. There was no evidence of tau pathology or changes in tau-regulatory proteins following five impacts, although some changes were observed following a single injury. Five impacts resulted in significant gait deficits, mild anhedonia and mild cognitive deficits at 9–12 months post-injury, effects not seen following a single injury. To the best of our knowledge, we are the first to describe chronic changes in metals and iron-regulatory proteins in a mouse model of r-mTBI, providing a strong indication towards an overall increase in brain iron levels (and other metals) in the chronic phase following r-mTBI. These results bring to question the relevance of tau and highlight the involvement of iron dysregulation in the development and/or progression of neurodegeneration following injury, which may lead to new therapeutic approaches in the future. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-023-01603-z. BioMed Central 2023-07-18 /pmc/articles/PMC10353227/ /pubmed/37464280 http://dx.doi.org/10.1186/s40478-023-01603-z Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/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 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
Juan, Sydney M. A.
Daglas, Maria
Truong, Phan H.
Mawal, Celeste
Adlard, Paul A.
Alterations in iron content, iron-regulatory proteins and behaviour without tau pathology at one year following repetitive mild traumatic brain injury
title Alterations in iron content, iron-regulatory proteins and behaviour without tau pathology at one year following repetitive mild traumatic brain injury
title_full Alterations in iron content, iron-regulatory proteins and behaviour without tau pathology at one year following repetitive mild traumatic brain injury
title_fullStr Alterations in iron content, iron-regulatory proteins and behaviour without tau pathology at one year following repetitive mild traumatic brain injury
title_full_unstemmed Alterations in iron content, iron-regulatory proteins and behaviour without tau pathology at one year following repetitive mild traumatic brain injury
title_short Alterations in iron content, iron-regulatory proteins and behaviour without tau pathology at one year following repetitive mild traumatic brain injury
title_sort alterations in iron content, iron-regulatory proteins and behaviour without tau pathology at one year following repetitive mild traumatic brain injury
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10353227/
https://www.ncbi.nlm.nih.gov/pubmed/37464280
http://dx.doi.org/10.1186/s40478-023-01603-z
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