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Rutin prevents tau pathology and neuroinflammation in a mouse model of Alzheimer’s disease

BACKGROUND: Tau pathology is a hallmark of Alzheimer’s disease (AD) and other tauopathies. During disease progression, abnormally phosphorylated forms of tau aggregate and accumulate into neurofibrillary tangles, leading to synapse loss, neuroinflammation, and neurodegeneration. Thus, targeting of t...

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Autores principales: Sun, Xiao-ying, Li, Ling-jie, Dong, Quan-Xiu, Zhu, Jie, Huang, Ya-ru, Hou, Sheng-jie, Yu, Xiao-lin, Liu, Rui-tian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196535/
https://www.ncbi.nlm.nih.gov/pubmed/34116706
http://dx.doi.org/10.1186/s12974-021-02182-3
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author Sun, Xiao-ying
Li, Ling-jie
Dong, Quan-Xiu
Zhu, Jie
Huang, Ya-ru
Hou, Sheng-jie
Yu, Xiao-lin
Liu, Rui-tian
author_facet Sun, Xiao-ying
Li, Ling-jie
Dong, Quan-Xiu
Zhu, Jie
Huang, Ya-ru
Hou, Sheng-jie
Yu, Xiao-lin
Liu, Rui-tian
author_sort Sun, Xiao-ying
collection PubMed
description BACKGROUND: Tau pathology is a hallmark of Alzheimer’s disease (AD) and other tauopathies. During disease progression, abnormally phosphorylated forms of tau aggregate and accumulate into neurofibrillary tangles, leading to synapse loss, neuroinflammation, and neurodegeneration. Thus, targeting of tau pathology is expected to be a promising strategy for AD treatment. METHODS: The effect of rutin on tau aggregation was detected by thioflavin T fluorescence and transmission electron microscope imaging. The effect of rutin on tau oligomer-induced cytotoxicity was assessed by MTT assay. The effect of rutin on tau oligomer-mediated the production of IL-1β and TNF-α in vitro was measured by ELISA. The uptake of extracellular tau by microglia was determined by immunocytochemistry. Six-month-old male Tau-P301S mice were treated with rutin or vehicle by oral administration daily for 30 days. The cognitive performance was determined using the Morris water maze test, Y-maze test, and novel object recognition test. The levels of pathological tau, gliosis, NF-kB activation, proinflammatory cytokines such as IL-1β and TNF-α, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunolabeling, immunoblotting, or ELISA. RESULTS: We showed that rutin, a natural flavonoid glycoside, inhibited tau aggregation and tau oligomer-induced cytotoxicity, lowered the production of proinflammatory cytokines, protected neuronal morphology from toxic tau oligomers, and promoted microglial uptake of extracellular tau oligomers in vitro. When applied to Tau-P301S mouse model of tauopathy, rutin reduced pathological tau levels, regulated tau hyperphosphorylation by increasing PP2A level, suppressed gliosis and neuroinflammation by downregulating NF-kB pathway, prevented microglial synapse engulfment, and rescued synapse loss in mouse brains, resulting in a significant improvement of cognition. CONCLUSION: In combination with the previously reported therapeutic effects of rutin on Aβ pathology, rutin is a promising drug candidate for AD treatment based its combinatorial targeting of tau and Aβ. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-021-02182-3.
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spelling pubmed-81965352021-06-15 Rutin prevents tau pathology and neuroinflammation in a mouse model of Alzheimer’s disease Sun, Xiao-ying Li, Ling-jie Dong, Quan-Xiu Zhu, Jie Huang, Ya-ru Hou, Sheng-jie Yu, Xiao-lin Liu, Rui-tian J Neuroinflammation Research BACKGROUND: Tau pathology is a hallmark of Alzheimer’s disease (AD) and other tauopathies. During disease progression, abnormally phosphorylated forms of tau aggregate and accumulate into neurofibrillary tangles, leading to synapse loss, neuroinflammation, and neurodegeneration. Thus, targeting of tau pathology is expected to be a promising strategy for AD treatment. METHODS: The effect of rutin on tau aggregation was detected by thioflavin T fluorescence and transmission electron microscope imaging. The effect of rutin on tau oligomer-induced cytotoxicity was assessed by MTT assay. The effect of rutin on tau oligomer-mediated the production of IL-1β and TNF-α in vitro was measured by ELISA. The uptake of extracellular tau by microglia was determined by immunocytochemistry. Six-month-old male Tau-P301S mice were treated with rutin or vehicle by oral administration daily for 30 days. The cognitive performance was determined using the Morris water maze test, Y-maze test, and novel object recognition test. The levels of pathological tau, gliosis, NF-kB activation, proinflammatory cytokines such as IL-1β and TNF-α, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunolabeling, immunoblotting, or ELISA. RESULTS: We showed that rutin, a natural flavonoid glycoside, inhibited tau aggregation and tau oligomer-induced cytotoxicity, lowered the production of proinflammatory cytokines, protected neuronal morphology from toxic tau oligomers, and promoted microglial uptake of extracellular tau oligomers in vitro. When applied to Tau-P301S mouse model of tauopathy, rutin reduced pathological tau levels, regulated tau hyperphosphorylation by increasing PP2A level, suppressed gliosis and neuroinflammation by downregulating NF-kB pathway, prevented microglial synapse engulfment, and rescued synapse loss in mouse brains, resulting in a significant improvement of cognition. CONCLUSION: In combination with the previously reported therapeutic effects of rutin on Aβ pathology, rutin is a promising drug candidate for AD treatment based its combinatorial targeting of tau and Aβ. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-021-02182-3. BioMed Central 2021-06-11 /pmc/articles/PMC8196535/ /pubmed/34116706 http://dx.doi.org/10.1186/s12974-021-02182-3 Text en © The Author(s) 2021 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
Sun, Xiao-ying
Li, Ling-jie
Dong, Quan-Xiu
Zhu, Jie
Huang, Ya-ru
Hou, Sheng-jie
Yu, Xiao-lin
Liu, Rui-tian
Rutin prevents tau pathology and neuroinflammation in a mouse model of Alzheimer’s disease
title Rutin prevents tau pathology and neuroinflammation in a mouse model of Alzheimer’s disease
title_full Rutin prevents tau pathology and neuroinflammation in a mouse model of Alzheimer’s disease
title_fullStr Rutin prevents tau pathology and neuroinflammation in a mouse model of Alzheimer’s disease
title_full_unstemmed Rutin prevents tau pathology and neuroinflammation in a mouse model of Alzheimer’s disease
title_short Rutin prevents tau pathology and neuroinflammation in a mouse model of Alzheimer’s disease
title_sort rutin prevents tau pathology and neuroinflammation in a mouse model of alzheimer’s disease
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196535/
https://www.ncbi.nlm.nih.gov/pubmed/34116706
http://dx.doi.org/10.1186/s12974-021-02182-3
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