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The involvement of NLRP3 inflammasome in CUMS-induced AD-like pathological changes and related cognitive decline in mice
BACKGROUND: Numerous studies have found that inhibiting the expression of NLRP3 inflammasome can significantly improve depressive-like behaviors in mice, but the research on its effect on cognitive decline in depression and its mechanism is still lacking. This study aimed to elucidate the role of NL...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173607/ https://www.ncbi.nlm.nih.gov/pubmed/37165444 http://dx.doi.org/10.1186/s12974-023-02791-0 |
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author | Li, Jia-Mei Hu, Ting Zhou, Xiao-Na Zhang, Ting Guo, Jia-Hui Wang, Min-Yuan Wu, Yi-Lin Su, Wen-Jun Jiang, Chun-Lei |
author_facet | Li, Jia-Mei Hu, Ting Zhou, Xiao-Na Zhang, Ting Guo, Jia-Hui Wang, Min-Yuan Wu, Yi-Lin Su, Wen-Jun Jiang, Chun-Lei |
author_sort | Li, Jia-Mei |
collection | PubMed |
description | BACKGROUND: Numerous studies have found that inhibiting the expression of NLRP3 inflammasome can significantly improve depressive-like behaviors in mice, but the research on its effect on cognitive decline in depression and its mechanism is still lacking. This study aimed to elucidate the role of NLRP3 inflammasome in cognitive decline in depression and explore the common neuro-immunological mechanisms of depression and Alzheimer’s disease (AD). METHODS: Male C57BL/6 mice were subjected to chronic unpredictable mild stress (CUMS) for 5 weeks, treatment group was administered with the NLRP3 inhibitor MCC950 (10 mg/kg, i.p.), fluoxetine served as positive control. Then, the mice were assessed for cognitive behaviors and depression-like behaviors, and changes of microglia and neurons in hippocampus and levels of Aβ metabolic pathway and tau protein were measured. To explore the mechanism of NLRP3 activation on neurons, we performed in vitro studies using BV2 microglia and mouse primary neurons. Furthermore, we focused on the role of NLRP3 inflammasome in the function of neurons and the expression of AD pathological indicators. RESULTS: CUMS induced depressive-like behaviors and cognitive decline in mice, which could be reversed by inhibiting NLRP3 inflammasome. MCC950, a specific NLRP3 inhibitor, alleviated CUMS-induced neuron injury and AD-like pathological changes, including the abnormal expression of Aβ metabolic pathway and the hyper-phosphorylation of tau protein. LPS (1 μg/mL) + ATP (1 mM) treatment activated the expression of NLRP3 inflammasome and IL-1β in vitro. In vitro experiment also proved that inhibiting the expression of NLRP3 inflammasome in microglia can restore the Aβ metabolic pathway to normal, decrease neuronal tau protein phosphorylation and protect neurons. CONCLUSIONS: Inhibition of NLRP3 inflammasome effectively alleviated CUMS-induced depressive-like behaviors and cognitive decline in mice, and inhibited the activation of AD physiological indicators. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02791-0. |
format | Online Article Text |
id | pubmed-10173607 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-101736072023-05-12 The involvement of NLRP3 inflammasome in CUMS-induced AD-like pathological changes and related cognitive decline in mice Li, Jia-Mei Hu, Ting Zhou, Xiao-Na Zhang, Ting Guo, Jia-Hui Wang, Min-Yuan Wu, Yi-Lin Su, Wen-Jun Jiang, Chun-Lei J Neuroinflammation Research BACKGROUND: Numerous studies have found that inhibiting the expression of NLRP3 inflammasome can significantly improve depressive-like behaviors in mice, but the research on its effect on cognitive decline in depression and its mechanism is still lacking. This study aimed to elucidate the role of NLRP3 inflammasome in cognitive decline in depression and explore the common neuro-immunological mechanisms of depression and Alzheimer’s disease (AD). METHODS: Male C57BL/6 mice were subjected to chronic unpredictable mild stress (CUMS) for 5 weeks, treatment group was administered with the NLRP3 inhibitor MCC950 (10 mg/kg, i.p.), fluoxetine served as positive control. Then, the mice were assessed for cognitive behaviors and depression-like behaviors, and changes of microglia and neurons in hippocampus and levels of Aβ metabolic pathway and tau protein were measured. To explore the mechanism of NLRP3 activation on neurons, we performed in vitro studies using BV2 microglia and mouse primary neurons. Furthermore, we focused on the role of NLRP3 inflammasome in the function of neurons and the expression of AD pathological indicators. RESULTS: CUMS induced depressive-like behaviors and cognitive decline in mice, which could be reversed by inhibiting NLRP3 inflammasome. MCC950, a specific NLRP3 inhibitor, alleviated CUMS-induced neuron injury and AD-like pathological changes, including the abnormal expression of Aβ metabolic pathway and the hyper-phosphorylation of tau protein. LPS (1 μg/mL) + ATP (1 mM) treatment activated the expression of NLRP3 inflammasome and IL-1β in vitro. In vitro experiment also proved that inhibiting the expression of NLRP3 inflammasome in microglia can restore the Aβ metabolic pathway to normal, decrease neuronal tau protein phosphorylation and protect neurons. CONCLUSIONS: Inhibition of NLRP3 inflammasome effectively alleviated CUMS-induced depressive-like behaviors and cognitive decline in mice, and inhibited the activation of AD physiological indicators. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02791-0. BioMed Central 2023-05-10 /pmc/articles/PMC10173607/ /pubmed/37165444 http://dx.doi.org/10.1186/s12974-023-02791-0 Text en © The Author(s) 2023 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 Li, Jia-Mei Hu, Ting Zhou, Xiao-Na Zhang, Ting Guo, Jia-Hui Wang, Min-Yuan Wu, Yi-Lin Su, Wen-Jun Jiang, Chun-Lei The involvement of NLRP3 inflammasome in CUMS-induced AD-like pathological changes and related cognitive decline in mice |
title | The involvement of NLRP3 inflammasome in CUMS-induced AD-like pathological changes and related cognitive decline in mice |
title_full | The involvement of NLRP3 inflammasome in CUMS-induced AD-like pathological changes and related cognitive decline in mice |
title_fullStr | The involvement of NLRP3 inflammasome in CUMS-induced AD-like pathological changes and related cognitive decline in mice |
title_full_unstemmed | The involvement of NLRP3 inflammasome in CUMS-induced AD-like pathological changes and related cognitive decline in mice |
title_short | The involvement of NLRP3 inflammasome in CUMS-induced AD-like pathological changes and related cognitive decline in mice |
title_sort | involvement of nlrp3 inflammasome in cums-induced ad-like pathological changes and related cognitive decline in mice |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173607/ https://www.ncbi.nlm.nih.gov/pubmed/37165444 http://dx.doi.org/10.1186/s12974-023-02791-0 |
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