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Repetitive mild TBI causes pTau aggregation in nigra without altering preexisting fibril induced Parkinson’s-like pathology burden

Population studies have shown that traumatic brain injury (TBI) is associated with an increased risk for Parkinson’s disease (PD) and among U.S. Veterans with a history of TBI this risk is 56% higher. The most common type of TBI is mild (mTBI) and often occurs repeatedly among athletes, military per...

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Autores principales: Delic, Vedad, Karp, Joshua H., Guzman, Maynard, Arismendi, Gabriel R., Stalnaker, Katherine J., Burton, Julia A., Murray, Kathleen E., Stamos, Joshua P., Beck, Kevin D., Sokratian, Arpine, West, Andrew B., Citron, Bruce A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9701434/
https://www.ncbi.nlm.nih.gov/pubmed/36435806
http://dx.doi.org/10.1186/s40478-022-01475-9
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author Delic, Vedad
Karp, Joshua H.
Guzman, Maynard
Arismendi, Gabriel R.
Stalnaker, Katherine J.
Burton, Julia A.
Murray, Kathleen E.
Stamos, Joshua P.
Beck, Kevin D.
Sokratian, Arpine
West, Andrew B.
Citron, Bruce A.
author_facet Delic, Vedad
Karp, Joshua H.
Guzman, Maynard
Arismendi, Gabriel R.
Stalnaker, Katherine J.
Burton, Julia A.
Murray, Kathleen E.
Stamos, Joshua P.
Beck, Kevin D.
Sokratian, Arpine
West, Andrew B.
Citron, Bruce A.
author_sort Delic, Vedad
collection PubMed
description Population studies have shown that traumatic brain injury (TBI) is associated with an increased risk for Parkinson’s disease (PD) and among U.S. Veterans with a history of TBI this risk is 56% higher. The most common type of TBI is mild (mTBI) and often occurs repeatedly among athletes, military personnel, and victims of domestic violence. PD is classically characterized by deficits in fine motor movement control resulting from progressive neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) midbrain region. This neurodegeneration is preceded by the predictable spread of characteristic alpha synuclein (αSyn) protein inclusions. Whether repetitive mTBI (r-mTBI) can nucleate PD pathology or accelerate prodromal PD pathology remains unknown. To answer this question, an injury device was constructed to deliver a surgery-free r-mTBI to rats and human-like PD pathology was induced by intracranial injection of recombinant αSyn preformed fibrils. At the 3-month endpoint, the r-mTBI caused encephalomalacia throughout the brain reminiscent of neuroimaging findings in patients with a history of mTBI, accompanied by astrocyte expansion and microglial activation. The pathology associated most closely with PD, which includes dopaminergic neurodegeneration in the SNpc and Lewy body-like αSyn inclusion burden in the surviving neurons, was not produced de novo by r-mTBI nor was the fibril induced preexisting pathology accelerated. r-mTBI did however cause aggregation of phosphorylated Tau (pTau) protein in nigra of rats with and without preexisting PD-like pathology. pTau aggregation was also found to colocalize with PFF induced αSyn pathology without r-mTBI. These findings suggest that r-mTBI induced pTau aggregate deposition in dopaminergic neurons may create an environment conducive to αSyn pathology nucleation and may add to preexisting proteinaceous aggregate burden. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-022-01475-9.
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spelling pubmed-97014342022-11-28 Repetitive mild TBI causes pTau aggregation in nigra without altering preexisting fibril induced Parkinson’s-like pathology burden Delic, Vedad Karp, Joshua H. Guzman, Maynard Arismendi, Gabriel R. Stalnaker, Katherine J. Burton, Julia A. Murray, Kathleen E. Stamos, Joshua P. Beck, Kevin D. Sokratian, Arpine West, Andrew B. Citron, Bruce A. Acta Neuropathol Commun Research Population studies have shown that traumatic brain injury (TBI) is associated with an increased risk for Parkinson’s disease (PD) and among U.S. Veterans with a history of TBI this risk is 56% higher. The most common type of TBI is mild (mTBI) and often occurs repeatedly among athletes, military personnel, and victims of domestic violence. PD is classically characterized by deficits in fine motor movement control resulting from progressive neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) midbrain region. This neurodegeneration is preceded by the predictable spread of characteristic alpha synuclein (αSyn) protein inclusions. Whether repetitive mTBI (r-mTBI) can nucleate PD pathology or accelerate prodromal PD pathology remains unknown. To answer this question, an injury device was constructed to deliver a surgery-free r-mTBI to rats and human-like PD pathology was induced by intracranial injection of recombinant αSyn preformed fibrils. At the 3-month endpoint, the r-mTBI caused encephalomalacia throughout the brain reminiscent of neuroimaging findings in patients with a history of mTBI, accompanied by astrocyte expansion and microglial activation. The pathology associated most closely with PD, which includes dopaminergic neurodegeneration in the SNpc and Lewy body-like αSyn inclusion burden in the surviving neurons, was not produced de novo by r-mTBI nor was the fibril induced preexisting pathology accelerated. r-mTBI did however cause aggregation of phosphorylated Tau (pTau) protein in nigra of rats with and without preexisting PD-like pathology. pTau aggregation was also found to colocalize with PFF induced αSyn pathology without r-mTBI. These findings suggest that r-mTBI induced pTau aggregate deposition in dopaminergic neurons may create an environment conducive to αSyn pathology nucleation and may add to preexisting proteinaceous aggregate burden. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-022-01475-9. BioMed Central 2022-11-26 /pmc/articles/PMC9701434/ /pubmed/36435806 http://dx.doi.org/10.1186/s40478-022-01475-9 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2022 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
Delic, Vedad
Karp, Joshua H.
Guzman, Maynard
Arismendi, Gabriel R.
Stalnaker, Katherine J.
Burton, Julia A.
Murray, Kathleen E.
Stamos, Joshua P.
Beck, Kevin D.
Sokratian, Arpine
West, Andrew B.
Citron, Bruce A.
Repetitive mild TBI causes pTau aggregation in nigra without altering preexisting fibril induced Parkinson’s-like pathology burden
title Repetitive mild TBI causes pTau aggregation in nigra without altering preexisting fibril induced Parkinson’s-like pathology burden
title_full Repetitive mild TBI causes pTau aggregation in nigra without altering preexisting fibril induced Parkinson’s-like pathology burden
title_fullStr Repetitive mild TBI causes pTau aggregation in nigra without altering preexisting fibril induced Parkinson’s-like pathology burden
title_full_unstemmed Repetitive mild TBI causes pTau aggregation in nigra without altering preexisting fibril induced Parkinson’s-like pathology burden
title_short Repetitive mild TBI causes pTau aggregation in nigra without altering preexisting fibril induced Parkinson’s-like pathology burden
title_sort repetitive mild tbi causes ptau aggregation in nigra without altering preexisting fibril induced parkinson’s-like pathology burden
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9701434/
https://www.ncbi.nlm.nih.gov/pubmed/36435806
http://dx.doi.org/10.1186/s40478-022-01475-9
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