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Longitudinal evaluation of neuroinflammation and oxidative stress in a mouse model of Alzheimer disease using positron emission tomography

BACKGROUND: Validation of new biomarkers of Alzheimer disease (AD) is crucial for the successful development and implementation of treatment strategies. Additional to traditional AT(N) biomarkers, neuroinflammation biomarkers, such as translocator protein (TSPO) and cystine/glutamine antiporter syst...

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Autores principales: Rejc, Luka, Gómez-Vallejo, Vanessa, Joya, Ana, Arsequell, Gemma, Egimendia, Ander, Castellnou, Pilar, Ríos-Anglada, Xabier, Cossío, Unai, Baz, Zuriñe, Iglesias, Leyre, Capetillo-Zarate, Estibaliz, Ramos-Cabrer, Pedro, Martin, Abraham, Llop, Jordi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9178858/
https://www.ncbi.nlm.nih.gov/pubmed/35676734
http://dx.doi.org/10.1186/s13195-022-01016-5
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author Rejc, Luka
Gómez-Vallejo, Vanessa
Joya, Ana
Arsequell, Gemma
Egimendia, Ander
Castellnou, Pilar
Ríos-Anglada, Xabier
Cossío, Unai
Baz, Zuriñe
Iglesias, Leyre
Capetillo-Zarate, Estibaliz
Ramos-Cabrer, Pedro
Martin, Abraham
Llop, Jordi
author_facet Rejc, Luka
Gómez-Vallejo, Vanessa
Joya, Ana
Arsequell, Gemma
Egimendia, Ander
Castellnou, Pilar
Ríos-Anglada, Xabier
Cossío, Unai
Baz, Zuriñe
Iglesias, Leyre
Capetillo-Zarate, Estibaliz
Ramos-Cabrer, Pedro
Martin, Abraham
Llop, Jordi
author_sort Rejc, Luka
collection PubMed
description BACKGROUND: Validation of new biomarkers of Alzheimer disease (AD) is crucial for the successful development and implementation of treatment strategies. Additional to traditional AT(N) biomarkers, neuroinflammation biomarkers, such as translocator protein (TSPO) and cystine/glutamine antiporter system (x(c)(-)), could be considered when assessing AD progression. Herein, we report the longitudinal investigation of [(18)F]DPA-714 and [(18)F]FSPG for their ability to detect TSPO and x(c)(-) biomarkers, respectively, in the 5xFAD mouse model for AD. METHODS: Expression of TSPO and x(c)(-) system was assessed longitudinally (2–12 months of age) on 5xFAD mice and their respective controls by positron emission tomography (PET) imaging using radioligands [(18)F]DPA-714 and [(18)F]FSPG. In parallel, in the same mice, amyloid-β plaque deposition was assessed with the amyloid PET radiotracer [(18)F]florbetaben. In vivo findings were correlated to ex vivo immunofluorescence staining of TSPO and x(c)(-) in microglia/macrophages and astrocytes on brain slices. Physiological changes of the brain tissue were assessed by magnetic resonance imaging (MRI) in 12-month-old mice. RESULTS: PET studies showed a significant increase in the uptake of [(18)F]DPA-714 and [(18)F]FSPG in the cortex, hippocampus, and thalamus in 5xFAD but not in WT mice over time. The results correlate with Aβ plaque deposition. Ex vivo staining confirmed higher TSPO overexpression in both, microglia/macrophages and astrocytes, and overexpression of x(c)(-) in non-glial cells of 5xFAD mice. Additionally, the results show that Aβ plaques were surrounded by microglia/macrophages overexpressing TSPO. MRI studies showed significant tissue shrinkage and microstructural alterations in 5xFAD mice compared to controls. CONCLUSIONS: TSPO and x(c)(-) overexpression can be assessed by [(18)F]DPA-714 and [(18)F]FSPG, respectively, and correlate with the level of Aβ plaque deposition obtained with a PET amyloid tracer. These results position the two tracers as promising imaging tools for the evaluation of disease progression. GRAPHICAL ABSTRACT: Longitudinal in vivo study in the 5xFAD mouse model shows that TSPO and oxidative stress assessment through [(18)F]DPA-714 and [(18)F]FSPG-PET imaging, respectively, could serve as a potential tool for the evaluation of Alzheimer disease progression. [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-022-01016-5.
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spelling pubmed-91788582022-06-10 Longitudinal evaluation of neuroinflammation and oxidative stress in a mouse model of Alzheimer disease using positron emission tomography Rejc, Luka Gómez-Vallejo, Vanessa Joya, Ana Arsequell, Gemma Egimendia, Ander Castellnou, Pilar Ríos-Anglada, Xabier Cossío, Unai Baz, Zuriñe Iglesias, Leyre Capetillo-Zarate, Estibaliz Ramos-Cabrer, Pedro Martin, Abraham Llop, Jordi Alzheimers Res Ther Research BACKGROUND: Validation of new biomarkers of Alzheimer disease (AD) is crucial for the successful development and implementation of treatment strategies. Additional to traditional AT(N) biomarkers, neuroinflammation biomarkers, such as translocator protein (TSPO) and cystine/glutamine antiporter system (x(c)(-)), could be considered when assessing AD progression. Herein, we report the longitudinal investigation of [(18)F]DPA-714 and [(18)F]FSPG for their ability to detect TSPO and x(c)(-) biomarkers, respectively, in the 5xFAD mouse model for AD. METHODS: Expression of TSPO and x(c)(-) system was assessed longitudinally (2–12 months of age) on 5xFAD mice and their respective controls by positron emission tomography (PET) imaging using radioligands [(18)F]DPA-714 and [(18)F]FSPG. In parallel, in the same mice, amyloid-β plaque deposition was assessed with the amyloid PET radiotracer [(18)F]florbetaben. In vivo findings were correlated to ex vivo immunofluorescence staining of TSPO and x(c)(-) in microglia/macrophages and astrocytes on brain slices. Physiological changes of the brain tissue were assessed by magnetic resonance imaging (MRI) in 12-month-old mice. RESULTS: PET studies showed a significant increase in the uptake of [(18)F]DPA-714 and [(18)F]FSPG in the cortex, hippocampus, and thalamus in 5xFAD but not in WT mice over time. The results correlate with Aβ plaque deposition. Ex vivo staining confirmed higher TSPO overexpression in both, microglia/macrophages and astrocytes, and overexpression of x(c)(-) in non-glial cells of 5xFAD mice. Additionally, the results show that Aβ plaques were surrounded by microglia/macrophages overexpressing TSPO. MRI studies showed significant tissue shrinkage and microstructural alterations in 5xFAD mice compared to controls. CONCLUSIONS: TSPO and x(c)(-) overexpression can be assessed by [(18)F]DPA-714 and [(18)F]FSPG, respectively, and correlate with the level of Aβ plaque deposition obtained with a PET amyloid tracer. These results position the two tracers as promising imaging tools for the evaluation of disease progression. GRAPHICAL ABSTRACT: Longitudinal in vivo study in the 5xFAD mouse model shows that TSPO and oxidative stress assessment through [(18)F]DPA-714 and [(18)F]FSPG-PET imaging, respectively, could serve as a potential tool for the evaluation of Alzheimer disease progression. [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-022-01016-5. BioMed Central 2022-06-09 /pmc/articles/PMC9178858/ /pubmed/35676734 http://dx.doi.org/10.1186/s13195-022-01016-5 Text en © The Author(s) 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
Rejc, Luka
Gómez-Vallejo, Vanessa
Joya, Ana
Arsequell, Gemma
Egimendia, Ander
Castellnou, Pilar
Ríos-Anglada, Xabier
Cossío, Unai
Baz, Zuriñe
Iglesias, Leyre
Capetillo-Zarate, Estibaliz
Ramos-Cabrer, Pedro
Martin, Abraham
Llop, Jordi
Longitudinal evaluation of neuroinflammation and oxidative stress in a mouse model of Alzheimer disease using positron emission tomography
title Longitudinal evaluation of neuroinflammation and oxidative stress in a mouse model of Alzheimer disease using positron emission tomography
title_full Longitudinal evaluation of neuroinflammation and oxidative stress in a mouse model of Alzheimer disease using positron emission tomography
title_fullStr Longitudinal evaluation of neuroinflammation and oxidative stress in a mouse model of Alzheimer disease using positron emission tomography
title_full_unstemmed Longitudinal evaluation of neuroinflammation and oxidative stress in a mouse model of Alzheimer disease using positron emission tomography
title_short Longitudinal evaluation of neuroinflammation and oxidative stress in a mouse model of Alzheimer disease using positron emission tomography
title_sort longitudinal evaluation of neuroinflammation and oxidative stress in a mouse model of alzheimer disease using positron emission tomography
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9178858/
https://www.ncbi.nlm.nih.gov/pubmed/35676734
http://dx.doi.org/10.1186/s13195-022-01016-5
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