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Neuroimmune proteins can differentiate between tauopathies
BACKGROUND: Tauopathies are a group of neurodegenerative diseases where there is pathologic accumulation of hyperphosphorylated tau protein (ptau). The most common tauopathy is Alzheimer’s disease (AD), but chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal de...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9675129/ https://www.ncbi.nlm.nih.gov/pubmed/36403052 http://dx.doi.org/10.1186/s12974-022-02640-6 |
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author | Cherry, Jonathan D. Baucom, Zach H. Eppich, Kaleb G. Kirsch, Daniel Dixon, Erin R. Tripodis, Yorghos Bieniek, Kevin F. Farrell, Kurt Whitney, Kristen Uretsky, Madeline Crary, John F. Dickson, Dennis McKee, Ann C. |
author_facet | Cherry, Jonathan D. Baucom, Zach H. Eppich, Kaleb G. Kirsch, Daniel Dixon, Erin R. Tripodis, Yorghos Bieniek, Kevin F. Farrell, Kurt Whitney, Kristen Uretsky, Madeline Crary, John F. Dickson, Dennis McKee, Ann C. |
author_sort | Cherry, Jonathan D. |
collection | PubMed |
description | BACKGROUND: Tauopathies are a group of neurodegenerative diseases where there is pathologic accumulation of hyperphosphorylated tau protein (ptau). The most common tauopathy is Alzheimer’s disease (AD), but chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and argyrophilic grain disease (AGD) are significant health risks as well. Currently, it is unclear what specific molecular factors might drive each distinct disease and represent therapeutic targets. Additionally, there is a lack of biomarkers that can differentiate each disease in life. Recent work has suggested that neuroinflammatory changes might be specific among distinct diseases and offers a novel resource for mechanistic targets and biomarker candidates. METHODS: To better examine each tauopathy, a 71 immune-related protein multiplex ELISA panel was utilized to analyze anterior cingulate grey matter from 127 individuals neuropathologically diagnosed with AD, CTE, PSP, CBD, and AGD. A partial least square regression analysis was carried out to perform unbiased clustering and identify proteins that are distinctly correlated with each tauopathy correcting for age and gender. Receiver operator characteristic and binary logistic regression analyses were then used to examine the ability of each candidate protein to distinguish diseases. Validation in postmortem cerebrospinal fluid (CSF) from 15 AD and 14 CTE cases was performed to determine if candidate proteins could act as possible novel biomarkers. RESULTS: Five clusters of immune proteins were identified and compared to each tauopathy to determine if clusters were specific to distinct disease. Each cluster was found to correlate with either CTE, AD, PSP, CBD, or AGD. When examining which proteins were the strongest driver of each cluster, it was observed the most distinctive protein for CTE was CCL21, AD was FLT3L, and PSP was IL13. Individual proteins that were specific to CBD and AGD were not observed. CCL21 was observed to be elevated in CTE CSF compared to AD cases (p = 0.02), further validating the use as possible biomarkers. Sub-analyses for male only cases confirmed the results were not skewed by gender differences. CONCLUSIONS: Overall, these results highlight that different neuroinflammatory responses might underlie unique mechanisms in related neurodegenerative pathologies. Additionally, the use of distinct neuroinflammatory signatures could help differentiate between tauopathies and act as novel biomarker candidate to increase specificity for in-life diagnoses. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-022-02640-6. |
format | Online Article Text |
id | pubmed-9675129 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-96751292022-11-20 Neuroimmune proteins can differentiate between tauopathies Cherry, Jonathan D. Baucom, Zach H. Eppich, Kaleb G. Kirsch, Daniel Dixon, Erin R. Tripodis, Yorghos Bieniek, Kevin F. Farrell, Kurt Whitney, Kristen Uretsky, Madeline Crary, John F. Dickson, Dennis McKee, Ann C. J Neuroinflammation Research BACKGROUND: Tauopathies are a group of neurodegenerative diseases where there is pathologic accumulation of hyperphosphorylated tau protein (ptau). The most common tauopathy is Alzheimer’s disease (AD), but chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and argyrophilic grain disease (AGD) are significant health risks as well. Currently, it is unclear what specific molecular factors might drive each distinct disease and represent therapeutic targets. Additionally, there is a lack of biomarkers that can differentiate each disease in life. Recent work has suggested that neuroinflammatory changes might be specific among distinct diseases and offers a novel resource for mechanistic targets and biomarker candidates. METHODS: To better examine each tauopathy, a 71 immune-related protein multiplex ELISA panel was utilized to analyze anterior cingulate grey matter from 127 individuals neuropathologically diagnosed with AD, CTE, PSP, CBD, and AGD. A partial least square regression analysis was carried out to perform unbiased clustering and identify proteins that are distinctly correlated with each tauopathy correcting for age and gender. Receiver operator characteristic and binary logistic regression analyses were then used to examine the ability of each candidate protein to distinguish diseases. Validation in postmortem cerebrospinal fluid (CSF) from 15 AD and 14 CTE cases was performed to determine if candidate proteins could act as possible novel biomarkers. RESULTS: Five clusters of immune proteins were identified and compared to each tauopathy to determine if clusters were specific to distinct disease. Each cluster was found to correlate with either CTE, AD, PSP, CBD, or AGD. When examining which proteins were the strongest driver of each cluster, it was observed the most distinctive protein for CTE was CCL21, AD was FLT3L, and PSP was IL13. Individual proteins that were specific to CBD and AGD were not observed. CCL21 was observed to be elevated in CTE CSF compared to AD cases (p = 0.02), further validating the use as possible biomarkers. Sub-analyses for male only cases confirmed the results were not skewed by gender differences. CONCLUSIONS: Overall, these results highlight that different neuroinflammatory responses might underlie unique mechanisms in related neurodegenerative pathologies. Additionally, the use of distinct neuroinflammatory signatures could help differentiate between tauopathies and act as novel biomarker candidate to increase specificity for in-life diagnoses. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-022-02640-6. BioMed Central 2022-11-19 /pmc/articles/PMC9675129/ /pubmed/36403052 http://dx.doi.org/10.1186/s12974-022-02640-6 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 Cherry, Jonathan D. Baucom, Zach H. Eppich, Kaleb G. Kirsch, Daniel Dixon, Erin R. Tripodis, Yorghos Bieniek, Kevin F. Farrell, Kurt Whitney, Kristen Uretsky, Madeline Crary, John F. Dickson, Dennis McKee, Ann C. Neuroimmune proteins can differentiate between tauopathies |
title | Neuroimmune proteins can differentiate between tauopathies |
title_full | Neuroimmune proteins can differentiate between tauopathies |
title_fullStr | Neuroimmune proteins can differentiate between tauopathies |
title_full_unstemmed | Neuroimmune proteins can differentiate between tauopathies |
title_short | Neuroimmune proteins can differentiate between tauopathies |
title_sort | neuroimmune proteins can differentiate between tauopathies |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9675129/ https://www.ncbi.nlm.nih.gov/pubmed/36403052 http://dx.doi.org/10.1186/s12974-022-02640-6 |
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