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Ultrasound-mediated augmented exosome release from astrocytes alleviates amyloid-β-induced neurotoxicity
Background: Extracellular vesicles, including exosomes, are secreted by a variety of cell types in the central nervous system. Exosomes play a role in removing intracellular materials from the endosomal system. Alzheimer's disease (AD) is caused by an overproduction or reduced amyloid-beta (Aβ)...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977450/ https://www.ncbi.nlm.nih.gov/pubmed/33754065 http://dx.doi.org/10.7150/thno.52436 |
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author | Deng, Zhiting Wang, Jieqiong Xiao, Yang Li, Fei Niu, Lili Liu, Xin Meng, Long Zheng, Hairong |
author_facet | Deng, Zhiting Wang, Jieqiong Xiao, Yang Li, Fei Niu, Lili Liu, Xin Meng, Long Zheng, Hairong |
author_sort | Deng, Zhiting |
collection | PubMed |
description | Background: Extracellular vesicles, including exosomes, are secreted by a variety of cell types in the central nervous system. Exosomes play a role in removing intracellular materials from the endosomal system. Alzheimer's disease (AD) is caused by an overproduction or reduced amyloid-beta (Aβ) peptide clearance. Increased Aβ levels in the brain may impair the exosome-mediated Aβ clearance pathway. Therapeutic ultrasound stimulation demonstrated its potential for promoting Aβ degradation efficiency in clinical trials. However, the underlying mechanism of ultrasound stimulation is still unclear. Methods: In this study, astrocytes, the most abundant glial cells in the brain, were used for exosome production. Post insonation, exosomes from ultrasound-stimulated HA cells (US-HA-Exo) were collected, nanoparticle tracking analysis and protein analysis were used to measure and characterize exosomes. Neuroprotective effect of US-HA-Exo in oligomeric Aβ(42) toxicated SH-SY5Y cells was tested. Cellular uptake and distribution of exosomes were observed by flow cytometry and confocal laser scanning microscopy. Focused ultrasound (FUS) with microbubbles was employed for blood-brain-barrier opening to achieve brain-targeted exosome delivery. After US-HA-Exo/FUS treatment, amyloid-β plaque in APP/PS1 mice were evaluated by Aβ immunostaining and thioflavin-S staining. Results: We showed that ultrasound resulted in an almost 5-fold increase in the exosome release from human astrocytes. Exosomes were rapidly internalized in SH-SY5Y cells, and colocalized with FITC-Aβ(42), causing a decreased uptake of FITC-Aβ(42). CCk-8 test results showed that US-HA-Exo could mitigate Aβ toxicity to neurons in vitro. The therapeutic potential of US-HA-Exo/FUS delivery was demonstrated by a decrease in thioflavin-S-positive amyloid plaques and Aβ immuno-staining, a therapeutic target for AD in APP/PS1 transgenic mice. The iTRAQ-based proteomic quantification was performed to gain mechanistic insight into the ultrasound effect on astrocyte-derived exosomes and their ability to alleviate Aβ neurotoxicity. Conclusion: Our results imply that US-HA-Exo have the potential to provide neuroprotective effects to reverse oligomeric amyloid-β-induced cytotoxicity in vitro and, when combined with FUS-induced BBB opening, enable the clearance of amyloid-β plaques in vivo. |
format | Online Article Text |
id | pubmed-7977450 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-79774502021-03-21 Ultrasound-mediated augmented exosome release from astrocytes alleviates amyloid-β-induced neurotoxicity Deng, Zhiting Wang, Jieqiong Xiao, Yang Li, Fei Niu, Lili Liu, Xin Meng, Long Zheng, Hairong Theranostics Research Paper Background: Extracellular vesicles, including exosomes, are secreted by a variety of cell types in the central nervous system. Exosomes play a role in removing intracellular materials from the endosomal system. Alzheimer's disease (AD) is caused by an overproduction or reduced amyloid-beta (Aβ) peptide clearance. Increased Aβ levels in the brain may impair the exosome-mediated Aβ clearance pathway. Therapeutic ultrasound stimulation demonstrated its potential for promoting Aβ degradation efficiency in clinical trials. However, the underlying mechanism of ultrasound stimulation is still unclear. Methods: In this study, astrocytes, the most abundant glial cells in the brain, were used for exosome production. Post insonation, exosomes from ultrasound-stimulated HA cells (US-HA-Exo) were collected, nanoparticle tracking analysis and protein analysis were used to measure and characterize exosomes. Neuroprotective effect of US-HA-Exo in oligomeric Aβ(42) toxicated SH-SY5Y cells was tested. Cellular uptake and distribution of exosomes were observed by flow cytometry and confocal laser scanning microscopy. Focused ultrasound (FUS) with microbubbles was employed for blood-brain-barrier opening to achieve brain-targeted exosome delivery. After US-HA-Exo/FUS treatment, amyloid-β plaque in APP/PS1 mice were evaluated by Aβ immunostaining and thioflavin-S staining. Results: We showed that ultrasound resulted in an almost 5-fold increase in the exosome release from human astrocytes. Exosomes were rapidly internalized in SH-SY5Y cells, and colocalized with FITC-Aβ(42), causing a decreased uptake of FITC-Aβ(42). CCk-8 test results showed that US-HA-Exo could mitigate Aβ toxicity to neurons in vitro. The therapeutic potential of US-HA-Exo/FUS delivery was demonstrated by a decrease in thioflavin-S-positive amyloid plaques and Aβ immuno-staining, a therapeutic target for AD in APP/PS1 transgenic mice. The iTRAQ-based proteomic quantification was performed to gain mechanistic insight into the ultrasound effect on astrocyte-derived exosomes and their ability to alleviate Aβ neurotoxicity. Conclusion: Our results imply that US-HA-Exo have the potential to provide neuroprotective effects to reverse oligomeric amyloid-β-induced cytotoxicity in vitro and, when combined with FUS-induced BBB opening, enable the clearance of amyloid-β plaques in vivo. Ivyspring International Publisher 2021-02-25 /pmc/articles/PMC7977450/ /pubmed/33754065 http://dx.doi.org/10.7150/thno.52436 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Deng, Zhiting Wang, Jieqiong Xiao, Yang Li, Fei Niu, Lili Liu, Xin Meng, Long Zheng, Hairong Ultrasound-mediated augmented exosome release from astrocytes alleviates amyloid-β-induced neurotoxicity |
title | Ultrasound-mediated augmented exosome release from astrocytes alleviates amyloid-β-induced neurotoxicity |
title_full | Ultrasound-mediated augmented exosome release from astrocytes alleviates amyloid-β-induced neurotoxicity |
title_fullStr | Ultrasound-mediated augmented exosome release from astrocytes alleviates amyloid-β-induced neurotoxicity |
title_full_unstemmed | Ultrasound-mediated augmented exosome release from astrocytes alleviates amyloid-β-induced neurotoxicity |
title_short | Ultrasound-mediated augmented exosome release from astrocytes alleviates amyloid-β-induced neurotoxicity |
title_sort | ultrasound-mediated augmented exosome release from astrocytes alleviates amyloid-β-induced neurotoxicity |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977450/ https://www.ncbi.nlm.nih.gov/pubmed/33754065 http://dx.doi.org/10.7150/thno.52436 |
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