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Enrichment of Neurodegenerative Microglia Signature in Brain-Derived Extracellular Vesicles Isolated from Alzheimer’s Disease Mouse Models

[Image: see text] Extracellular vesicles (EVs) are secreted by any neural cells in the central nervous system for molecular clearance, cellular communications, and disease spread in multiple neurodegenerative diseases, including Alzheimer’s disease (AD), although their exact molecular mechanism is p...

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Autores principales: Muraoka, Satoshi, Jedrychowski, Mark P., Iwahara, Naotoshi, Abdullah, Mohammad, Onos, Kristen D., Keezer, Kelly J., Hu, Jianqiao, Ikezu, Seiko, Howell, Gareth R., Gygi, Steven P., Ikezu, Tsuneya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2021
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944570/
https://www.ncbi.nlm.nih.gov/pubmed/33534581
http://dx.doi.org/10.1021/acs.jproteome.0c00934
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author Muraoka, Satoshi
Jedrychowski, Mark P.
Iwahara, Naotoshi
Abdullah, Mohammad
Onos, Kristen D.
Keezer, Kelly J.
Hu, Jianqiao
Ikezu, Seiko
Howell, Gareth R.
Gygi, Steven P.
Ikezu, Tsuneya
author_facet Muraoka, Satoshi
Jedrychowski, Mark P.
Iwahara, Naotoshi
Abdullah, Mohammad
Onos, Kristen D.
Keezer, Kelly J.
Hu, Jianqiao
Ikezu, Seiko
Howell, Gareth R.
Gygi, Steven P.
Ikezu, Tsuneya
author_sort Muraoka, Satoshi
collection PubMed
description [Image: see text] Extracellular vesicles (EVs) are secreted by any neural cells in the central nervous system for molecular clearance, cellular communications, and disease spread in multiple neurodegenerative diseases, including Alzheimer’s disease (AD), although their exact molecular mechanism is poorly understood. We hypothesize that high-resolution proteomic profiling of EVs separated from animal models of AD would determine the composition of EV contents and their cellular origin. Here, we examined recently developed transgenic mice (CAST.APP/PS1), which express familial AD-linked mutations of amyloid precursor protein (APP) and presenilin-1 (PS1) in the CAST/EiJ mouse strain and develop hippocampal neurodegeneration. Quantitative proteomics analysis of EVs separated from CAST.APP/PS1 and age-matched control mice by tandem mass tag-mass spectrometry identified a total of 3444 unique proteins, which are enriched in neuron-, astrocyte-, oligodendrocyte-, and microglia-specific molecules. CAST.APP/PS1-derived EVs show significant enrichment of Psen1, APP, and Itgax and reduction of Wdr61, Pmpca, Aldh1a2, Calu, Anp32b, Actn4, and Ndufv2 compared to WT-derived EVs, suggesting the involvement of Aβ-processing complex and disease-associated/neurodegenerative microglia (DAM/MGnD) in EV secretion. In addition, Itgax and Apoe, DAM/MGnD markers, in EVs show a positive correlation with Itgax and Apoe mRNA expression from brain tissue in CAST.APP/PS1 mice. These datasets indicate the significant contribution of Aβ plaque and neurodegeneration-induced DAM/MGnD microglia for EV secretion in CAST.APP/PS1 mice and shed light on understanding AD pathogenesis.
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spelling pubmed-79445702021-03-11 Enrichment of Neurodegenerative Microglia Signature in Brain-Derived Extracellular Vesicles Isolated from Alzheimer’s Disease Mouse Models Muraoka, Satoshi Jedrychowski, Mark P. Iwahara, Naotoshi Abdullah, Mohammad Onos, Kristen D. Keezer, Kelly J. Hu, Jianqiao Ikezu, Seiko Howell, Gareth R. Gygi, Steven P. Ikezu, Tsuneya J Proteome Res [Image: see text] Extracellular vesicles (EVs) are secreted by any neural cells in the central nervous system for molecular clearance, cellular communications, and disease spread in multiple neurodegenerative diseases, including Alzheimer’s disease (AD), although their exact molecular mechanism is poorly understood. We hypothesize that high-resolution proteomic profiling of EVs separated from animal models of AD would determine the composition of EV contents and their cellular origin. Here, we examined recently developed transgenic mice (CAST.APP/PS1), which express familial AD-linked mutations of amyloid precursor protein (APP) and presenilin-1 (PS1) in the CAST/EiJ mouse strain and develop hippocampal neurodegeneration. Quantitative proteomics analysis of EVs separated from CAST.APP/PS1 and age-matched control mice by tandem mass tag-mass spectrometry identified a total of 3444 unique proteins, which are enriched in neuron-, astrocyte-, oligodendrocyte-, and microglia-specific molecules. CAST.APP/PS1-derived EVs show significant enrichment of Psen1, APP, and Itgax and reduction of Wdr61, Pmpca, Aldh1a2, Calu, Anp32b, Actn4, and Ndufv2 compared to WT-derived EVs, suggesting the involvement of Aβ-processing complex and disease-associated/neurodegenerative microglia (DAM/MGnD) in EV secretion. In addition, Itgax and Apoe, DAM/MGnD markers, in EVs show a positive correlation with Itgax and Apoe mRNA expression from brain tissue in CAST.APP/PS1 mice. These datasets indicate the significant contribution of Aβ plaque and neurodegeneration-induced DAM/MGnD microglia for EV secretion in CAST.APP/PS1 mice and shed light on understanding AD pathogenesis. American Chemical Society 2021-02-03 2021-03-05 /pmc/articles/PMC7944570/ /pubmed/33534581 http://dx.doi.org/10.1021/acs.jproteome.0c00934 Text en © 2021 The Authors. Published by American Chemical Society This is an open access article published under an ACS AuthorChoice License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Muraoka, Satoshi
Jedrychowski, Mark P.
Iwahara, Naotoshi
Abdullah, Mohammad
Onos, Kristen D.
Keezer, Kelly J.
Hu, Jianqiao
Ikezu, Seiko
Howell, Gareth R.
Gygi, Steven P.
Ikezu, Tsuneya
Enrichment of Neurodegenerative Microglia Signature in Brain-Derived Extracellular Vesicles Isolated from Alzheimer’s Disease Mouse Models
title Enrichment of Neurodegenerative Microglia Signature in Brain-Derived Extracellular Vesicles Isolated from Alzheimer’s Disease Mouse Models
title_full Enrichment of Neurodegenerative Microglia Signature in Brain-Derived Extracellular Vesicles Isolated from Alzheimer’s Disease Mouse Models
title_fullStr Enrichment of Neurodegenerative Microglia Signature in Brain-Derived Extracellular Vesicles Isolated from Alzheimer’s Disease Mouse Models
title_full_unstemmed Enrichment of Neurodegenerative Microglia Signature in Brain-Derived Extracellular Vesicles Isolated from Alzheimer’s Disease Mouse Models
title_short Enrichment of Neurodegenerative Microglia Signature in Brain-Derived Extracellular Vesicles Isolated from Alzheimer’s Disease Mouse Models
title_sort enrichment of neurodegenerative microglia signature in brain-derived extracellular vesicles isolated from alzheimer’s disease mouse models
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944570/
https://www.ncbi.nlm.nih.gov/pubmed/33534581
http://dx.doi.org/10.1021/acs.jproteome.0c00934
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