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Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 mice
BACKGROUND: The neuropathological hallmarks of Alzheimer’s disease (AD) are amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). The amyloid cascade theory is the leading hypothesis of AD pathology. Aβ deposition precedes the aggregation of tau pathology and Aβ pathology precipitates tau patho...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871393/ https://www.ncbi.nlm.nih.gov/pubmed/33563332 http://dx.doi.org/10.1186/s13195-020-00761-9 |
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author | Chen, Yanxing Zhao, Shuai Fan, Ziqi Li, Zheyu Zhu, Yueli Shen, Ting Li, Kaicheng Yan, Yaping Tian, Jun Liu, Zhirong Zhang, Baorong |
author_facet | Chen, Yanxing Zhao, Shuai Fan, Ziqi Li, Zheyu Zhu, Yueli Shen, Ting Li, Kaicheng Yan, Yaping Tian, Jun Liu, Zhirong Zhang, Baorong |
author_sort | Chen, Yanxing |
collection | PubMed |
description | BACKGROUND: The neuropathological hallmarks of Alzheimer’s disease (AD) are amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). The amyloid cascade theory is the leading hypothesis of AD pathology. Aβ deposition precedes the aggregation of tau pathology and Aβ pathology precipitates tau pathology. Evidence also indicates the reciprocal interactions between amyloid and tau pathology. However, the detailed relationship between amyloid and tau pathology in AD remains elusive. Metformin might have a positive effect on cognitive impairments. However, whether metformin can reduce AD-related pathologies is still unconclusive. METHODS: Brain extracts containing tau aggregates were unilaterally injected into the hippocampus and the overlying cerebral cortex of 9-month-old APPswe/PS1DE9 (APP/PS1) mice and age-matched wild-type (WT) mice. Metformin was administrated in the drinking water for 2 months. Aβ pathology, tau pathology, plaque-associated microgliosis, and autophagy marker were analyzed by immunohistochemical staining and immunofluorescence analysis 2 months after injection of proteopathic tau seeds. The effects of metformin on both pathologies were explored. RESULTS: We observed tau aggregates in dystrophic neurites surrounding Aβ plaques (NP tau) in the bilateral hippocampi and cortices of tau-injected APP/PS1 mice but not WT mice. Aβ plaques promoted the aggregation of NP tau pathology. Injection of proteopathic tau seeds exacerbated Aβ deposits and decreased the number of microglia around Aβ plaques in the hippocampus and cortex of APP/PS1 mice. Metformin ameliorated the microglial autophagy impairment, increased the number of microglia around Aβ plaques, promoted the phagocytosis of NP tau, and reduced Aβ load and NP tau pathology in APP/PS1 mice. CONCLUSION: These findings indicate the existence of the crosstalk between amyloid and NP tau pathology. Metformin promoted the phagocytosis of pathological Aβ and tau proteins by enhancing microglial autophagy capability. It reduced Aβ deposits and limited the spreading of NP tau pathology in APP/PS1 mice, which exerts a beneficial effect on both pathologies. |
format | Online Article Text |
id | pubmed-7871393 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-78713932021-02-09 Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 mice Chen, Yanxing Zhao, Shuai Fan, Ziqi Li, Zheyu Zhu, Yueli Shen, Ting Li, Kaicheng Yan, Yaping Tian, Jun Liu, Zhirong Zhang, Baorong Alzheimers Res Ther Research BACKGROUND: The neuropathological hallmarks of Alzheimer’s disease (AD) are amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). The amyloid cascade theory is the leading hypothesis of AD pathology. Aβ deposition precedes the aggregation of tau pathology and Aβ pathology precipitates tau pathology. Evidence also indicates the reciprocal interactions between amyloid and tau pathology. However, the detailed relationship between amyloid and tau pathology in AD remains elusive. Metformin might have a positive effect on cognitive impairments. However, whether metformin can reduce AD-related pathologies is still unconclusive. METHODS: Brain extracts containing tau aggregates were unilaterally injected into the hippocampus and the overlying cerebral cortex of 9-month-old APPswe/PS1DE9 (APP/PS1) mice and age-matched wild-type (WT) mice. Metformin was administrated in the drinking water for 2 months. Aβ pathology, tau pathology, plaque-associated microgliosis, and autophagy marker were analyzed by immunohistochemical staining and immunofluorescence analysis 2 months after injection of proteopathic tau seeds. The effects of metformin on both pathologies were explored. RESULTS: We observed tau aggregates in dystrophic neurites surrounding Aβ plaques (NP tau) in the bilateral hippocampi and cortices of tau-injected APP/PS1 mice but not WT mice. Aβ plaques promoted the aggregation of NP tau pathology. Injection of proteopathic tau seeds exacerbated Aβ deposits and decreased the number of microglia around Aβ plaques in the hippocampus and cortex of APP/PS1 mice. Metformin ameliorated the microglial autophagy impairment, increased the number of microglia around Aβ plaques, promoted the phagocytosis of NP tau, and reduced Aβ load and NP tau pathology in APP/PS1 mice. CONCLUSION: These findings indicate the existence of the crosstalk between amyloid and NP tau pathology. Metformin promoted the phagocytosis of pathological Aβ and tau proteins by enhancing microglial autophagy capability. It reduced Aβ deposits and limited the spreading of NP tau pathology in APP/PS1 mice, which exerts a beneficial effect on both pathologies. BioMed Central 2021-02-09 /pmc/articles/PMC7871393/ /pubmed/33563332 http://dx.doi.org/10.1186/s13195-020-00761-9 Text en © The Author(s) 2021 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/. The Creative Commons Public Domain Dedication waiver (http://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 Chen, Yanxing Zhao, Shuai Fan, Ziqi Li, Zheyu Zhu, Yueli Shen, Ting Li, Kaicheng Yan, Yaping Tian, Jun Liu, Zhirong Zhang, Baorong Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 mice |
title | Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 mice |
title_full | Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 mice |
title_fullStr | Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 mice |
title_full_unstemmed | Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 mice |
title_short | Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 mice |
title_sort | metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in app/ps1 mice |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871393/ https://www.ncbi.nlm.nih.gov/pubmed/33563332 http://dx.doi.org/10.1186/s13195-020-00761-9 |
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