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Upregulation of neuronal PGC-1α ameliorates cognitive impairment induced by chronic cerebral hypoperfusion

Rationale: Mitochondrial dysfunction and oxidative stress occur in vascular dementia (VaD), but the specific molecular mechanism regulating these events remains unclear. Peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α) is a master regulator for mitochondrial function. This study...

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Autores principales: Han, Bin, Jiang, Wei, Liu, Haijie, Wang, Junjie, Zheng, Kai, Cui, Pan, Feng, Yan, Dang, Chun, Bu, Yali, Wang, Qing Mei, Ju, Zhenyu, Hao, Junwei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052889/
https://www.ncbi.nlm.nih.gov/pubmed/32194838
http://dx.doi.org/10.7150/thno.37119
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author Han, Bin
Jiang, Wei
Liu, Haijie
Wang, Junjie
Zheng, Kai
Cui, Pan
Feng, Yan
Dang, Chun
Bu, Yali
Wang, Qing Mei
Ju, Zhenyu
Hao, Junwei
author_facet Han, Bin
Jiang, Wei
Liu, Haijie
Wang, Junjie
Zheng, Kai
Cui, Pan
Feng, Yan
Dang, Chun
Bu, Yali
Wang, Qing Mei
Ju, Zhenyu
Hao, Junwei
author_sort Han, Bin
collection PubMed
description Rationale: Mitochondrial dysfunction and oxidative stress occur in vascular dementia (VaD), but the specific molecular mechanism regulating these events remains unclear. Peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α) is a master regulator for mitochondrial function. This study aims to investigate whether PGC-1α is involved in the pathophysiology of VaD. Methods: We firstly generated PGC-1α(f/f) Eno2-Cre mice to induce neuron-specific overexpression of PGC-1α by crossbreeding PGC-1α(f/f) mice with Eno2-cre mice. Then, the mice were subjected to bilateral common carotid artery stenosis to induce chronic cerebral hypoperfusion. Neurological function and hippocampal PGC-1α expression was evaluated. Next, RNA-Seq analysis and Seahorse assay were performed on the hippocampal neurons. In addition, mitochondrial antioxidants, uncoupling proteins, ROS production and the activation of glial cells were also measured. Results: Our results showed that hippocampal PGC-1α expression is down-regulated in the mouse VaD model induced by chronic cerebral hypoperfusion. In contrast, neuronal PGC-1α overexpression significantly ameliorated cognitive deficits. RNA-Seq analysis indicated that PGC-1α improved energy metabolism of neurons under hypoxic condition, and Seahorse assay confirmed that PGC-1α increases the metabolic activity of neurons. Further study demonstrated that PGC-1α boosted the expressions of mitochondrial antioxidants and uncoupling proteins (UCPs), including SOD2, Prx3, GPx1, UCP2, UCP4 and UCP5, which in turn reduced reactive oxygen species (ROS) production. Moreover, the activation of microglia and astrocytes was also found to decrease in the hippocampus. All of these changes greatly contributed to protect hippocampal neurons against ischemic insults. Conclusions: PGC-1α could suppress the excessive ROS and neuroinflammation in the hippocampus, opening up a potential therapeutic target for cognitive impairment.
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spelling pubmed-70528892020-03-19 Upregulation of neuronal PGC-1α ameliorates cognitive impairment induced by chronic cerebral hypoperfusion Han, Bin Jiang, Wei Liu, Haijie Wang, Junjie Zheng, Kai Cui, Pan Feng, Yan Dang, Chun Bu, Yali Wang, Qing Mei Ju, Zhenyu Hao, Junwei Theranostics Research Paper Rationale: Mitochondrial dysfunction and oxidative stress occur in vascular dementia (VaD), but the specific molecular mechanism regulating these events remains unclear. Peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α) is a master regulator for mitochondrial function. This study aims to investigate whether PGC-1α is involved in the pathophysiology of VaD. Methods: We firstly generated PGC-1α(f/f) Eno2-Cre mice to induce neuron-specific overexpression of PGC-1α by crossbreeding PGC-1α(f/f) mice with Eno2-cre mice. Then, the mice were subjected to bilateral common carotid artery stenosis to induce chronic cerebral hypoperfusion. Neurological function and hippocampal PGC-1α expression was evaluated. Next, RNA-Seq analysis and Seahorse assay were performed on the hippocampal neurons. In addition, mitochondrial antioxidants, uncoupling proteins, ROS production and the activation of glial cells were also measured. Results: Our results showed that hippocampal PGC-1α expression is down-regulated in the mouse VaD model induced by chronic cerebral hypoperfusion. In contrast, neuronal PGC-1α overexpression significantly ameliorated cognitive deficits. RNA-Seq analysis indicated that PGC-1α improved energy metabolism of neurons under hypoxic condition, and Seahorse assay confirmed that PGC-1α increases the metabolic activity of neurons. Further study demonstrated that PGC-1α boosted the expressions of mitochondrial antioxidants and uncoupling proteins (UCPs), including SOD2, Prx3, GPx1, UCP2, UCP4 and UCP5, which in turn reduced reactive oxygen species (ROS) production. Moreover, the activation of microglia and astrocytes was also found to decrease in the hippocampus. All of these changes greatly contributed to protect hippocampal neurons against ischemic insults. Conclusions: PGC-1α could suppress the excessive ROS and neuroinflammation in the hippocampus, opening up a potential therapeutic target for cognitive impairment. Ivyspring International Publisher 2020-02-03 /pmc/articles/PMC7052889/ /pubmed/32194838 http://dx.doi.org/10.7150/thno.37119 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
Han, Bin
Jiang, Wei
Liu, Haijie
Wang, Junjie
Zheng, Kai
Cui, Pan
Feng, Yan
Dang, Chun
Bu, Yali
Wang, Qing Mei
Ju, Zhenyu
Hao, Junwei
Upregulation of neuronal PGC-1α ameliorates cognitive impairment induced by chronic cerebral hypoperfusion
title Upregulation of neuronal PGC-1α ameliorates cognitive impairment induced by chronic cerebral hypoperfusion
title_full Upregulation of neuronal PGC-1α ameliorates cognitive impairment induced by chronic cerebral hypoperfusion
title_fullStr Upregulation of neuronal PGC-1α ameliorates cognitive impairment induced by chronic cerebral hypoperfusion
title_full_unstemmed Upregulation of neuronal PGC-1α ameliorates cognitive impairment induced by chronic cerebral hypoperfusion
title_short Upregulation of neuronal PGC-1α ameliorates cognitive impairment induced by chronic cerebral hypoperfusion
title_sort upregulation of neuronal pgc-1α ameliorates cognitive impairment induced by chronic cerebral hypoperfusion
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052889/
https://www.ncbi.nlm.nih.gov/pubmed/32194838
http://dx.doi.org/10.7150/thno.37119
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