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

ABSTRACT: 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-? co-activator-1? (PGC-1?) is a master regulator for mitochondrial function. This study aims to investigate whether PGC-1? is involved in the pathophysiology of VaD. Methods: We firstly generated PGC-1? f/f Eno2-Cre mice to induce neuron-specific overexpression of PGC-1? by crossbreeding PGC-1? 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-1? 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-1? expression is down-regulated in the mouse VaD model induced by chronic cerebral hypoperfusion. In contrast, neuronal PGC-1? overexpression significantly ameliorated cognitive deficits. RNA-Seq analysis indicated that PGC-1? improved energy metabolism of neurons under hypoxic condition, and Seahorse assay confirmed that PGC-1? increases the metabolic activity of neurons. Further study demonstrated that PGC-1? 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-1? could suppress the excessive ROS and neuroinflammation in the hippocampus, opening up a potential therapeutic target for cognitive impairment.

SUBMITTER: Han B

PROVIDER: S-EPMC7052889 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Han Bin B Jiang Wei W Liu Haijie H Wang Junjie J Zheng Kai K Cui Pan P Feng Yan Y Dang Chun C Bu Yali Y Wang Qing Mei QM Ju Zhenyu Z Hao Junwei J

Theranostics 20200203 6

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-1αf/f Eno2-Cre mice to induce neuron-specific overexpre ...[more]

PMID: 32194838

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Project description:Objective:Currently, most models of vascular cognitive impairment are established by occluding the carotid arteries uni- or bilaterally to reduce the cerebral blood flow mimicking chronic cerebral hypoxia. Due to the sudden blood flow interruption, a gradual narrowing of the carotid artery cannot be completely imitated. This paper aims to establish a bilateral carotid stenosis model with mild cognitive dysfunction and mild white matter changes to simulate patients with vascular predementia. Methods:Aged Wistar rats (18 months old) underwent either bilateral common carotid artery stenosis (BCAS) or occlusion (BCAO) surgery or a sham operation (control group). The cerebral blood flow in the frontal cortex was measured using Doppler flowmetry. Thirty days after surgery, cognitive function impairments were determined with the Morris water maze; cerebral magnetic resonance imaging was performed to detect changes in fractional anisotropy to assess white matter injuries, and histological studies were performed. Results:The aged rats in the BCAS group showed a more gradual cerebral blood flow reduction and a lower mortality rate (11%) compared to rats in the BCAO group. The water maze test revealed a more marginal impairment affecting spatial learning and memory in rats with BCAS than in rats with BCAO. Diffusion tensor imaging detected white matter injuries in the hippocampus and cerebral cortex of BCAS rats. Particularly, a small portion of nerve fibers of the lateral somatosensory cortex was significantly different between rats of the BCAO and BCAS groups. In the BCAS group, the microscopic structure of the hippocampal CA1 region changed slightly after 30 days and sustained a slight mitochondrial crista crack. Fluorescence staining indicated that the number of GFAP-positive cells was increased in rat brains of the BCAS group, and this phenomenon was even more pronounced in the BCAO group. The hnRNPA2/B1 and GABAAR-?1 expression levels were significantly decreased in the hippocampus of rats with BCAS compared to those of controls. Conclusion:Severe bilateral carotid stenosis induced mild cognitive dysfunction and slight structural changes in the brains of aged rats. Thus, a chronic cerebral hypoperfusion model was successfully established.

Dataset Information

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

Publications

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

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