Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Psychiatry. Sep 19, 2023; 13(9): 630-644
Published online Sep 19, 2023. doi: 10.5498/wjp.v13.i9.630
Exosomal miR-320e through wnt2targeted inhibition of the Wnt/β-catenin pathway allevisate cerebral small vessel disease and cognitive impairment
Zheng Wang, Xue-Ning Li, Shao-Nan Yang, Yuan Wang, Ke-Jin Gao, Bin Han, Ai-Jun Ma
Zheng Wang, Department of Internal Medicine-Neurology, Affiliated Hospital of Qingdao University, Qingdao 266001, Shandong Province, China
Xue-Ning Li, Shao-Nan Yang, Yuan Wang, Ke-Jin Gao, Bin Han, Ai-Jun Ma, Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao 266001, Shandong Province, China
Author contributions: Wang Z and Li XN concepted the study; Wang Z, Yang SN and Wang Y collected the data; Wang Z, Gao KJ, Han B and Ma AJ contributed to the formal analysis; Wang Z and Ma AJ contributed to the investigation; Wang Z, Li XN and Wang Y contributed to the methodology; Wang Z, Han B, Gao KJ and Ma AJ supervised the study; Yang SN validated the study; Wang Z and Yang SN contributed to the visualization of the study; Wang Z and Han B originally drafted the manuscript; Wang Z, Li XN, Yang SN, Wang Y Gao KJ Han B and Ma AJ reviewed and edited the manuscript.
Institutional review board statement: The study has passed the ethical review of Qingdao University Affiliated Hospital.
Informed consent statement: All specimens were collected after obtaining authorization from the patients and their families and signing a consent form.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: All data generated and analyzed during the study are included in this published article. The datasets generated and/or analyzed in the current study are also available from the NCBI repository https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE217872
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Ai-Jun Ma, MD, Attending Doctor, Department of Neurology, The Affiliated Hospital of Qingdao University, No.16 Jiangsu Street, Qingdao 266001, Shandong Province, China. drmaj@qdu.edu.cn
Received: May 24, 2023
Peer-review started: May 24, 2023
First decision: June 12, 2023
Revised: June 20, 2023
Accepted: July 14, 2023
Article in press: July 14, 2023
Published online: September 19, 2023
Processing time: 114 Days and 9.2 Hours
ARTICLE HIGHLIGHTS
Research background

Cerebral small vessel disease (CVSD) is a common neurodegenerative disorder characterized by cognitive impairment and depression. Exosomal miRNAs play an essential role in the pathophysiology of CVSD, and their dysregulation contributes to disease progression. This study aimed to investigate the potential role of exosomal miR-320e in the Wnt/β-catenin pathway stimulated by oxidative stress and its clinical correlation with cognitive impairment and depression in patients with CVSD. The study utilized high-throughput sequencing, bioinformatics analysis, dual-luciferase reporter gene experiments, and retrospective analysis among patients with CVSD. The aim was to explore whether exosomal miR-320e could suppress the Wnt/β-catenin pathway and play a protective role in CVSD progression, as well as examine its potential correlation with cognitive impairment and depression in patients with CVSD. The findings suggest that exosomal miR-320e targets Wnt2 and inhibits the Wnt/β-catenin pathway in response to oxidative stress, potentially playing a protective role in CVSD progression. Elevated miR-320e expression may also correlate with less severe cognitive impairment and depression in patients with CVSD.

Research motivation

CVSD is a complex neurodegenerative disorder that affects cognitive function and mental health, but currently lacks effective treatments. Exosomal miRNAs are emerging as important regulators of physiological and pathological processes in the brain, including CVSD. This study aimed to investigate the potential role of exosomal miR-320e in the Wnt/β-catenin pathway stimulated by oxidative stress and its clinical correlation with cognitive impairment and depression in patients with CVSD. The study utilized high-throughput sequencing, bioinformatics analysis, dual-luciferase reporter gene experiments, and retrospective analysis among patients with CVSD. The aim was to explore whether exosomal miR-320e could suppress the Wnt/β-catenin pathway and play a protective role in CVSD progression, as well as examine its potential correlation with cognitive impairment and depression in patients with CVSD. The findings suggest that exosomal miR-320e has a potentially protective role in CVSD progression and may be a novel therapeutic target. The study provides further insights into the complex pathophysiology of CVSD and highlights the importance of exosomal miRNAs in neurological diseases.

Research objectives

The research objectives of this study were to explore the potential role of exosomal miR-320e in the Wnt/β-catenin pathway stimulated by oxidative stress and its clinical correlation with cognitive impairment and depression in patients with cerebral small vessel disease (CVSD). The study aimed to identify differentially expressed exosomal miRNAs by sequencing plasma exosomes from patients with CVSD and healthy controls, confirm the binding of miR-320e to Wnt2 through bioinformatics and dual luciferase analyses, evaluate the mRNA and protein levels of downstream components in the Wnt/β-catenin pathway when overexpressed or knocked down miR-320e under H2O2-induced oxidative stress, and conduct a retrospective analysis among patients with CVSD to confirm the relationship between miR-320e expression and the severity of cognitive impairment and depression. The study also aimed to investigate whether exosomal miR-320e could inhibit the Wnt/β-catenin pathway and play a protective role in CVSD progression, potentially leading to the development of novel therapeutic targets for this complex neurodegenerative disorder.

Research methods

The study utilized various methods to investigate the role of exosomal miR-320e in CVSD. Differentially expressed exosomal miRNAs were identified by sequencing plasma exosomes from patients with CVSD and healthy controls. Bioinformatics analysis and dual-luciferase reporter gene experiments were conducted to confirm the binding of miR-320e to Wnt2. The mRNA and protein levels of downstream components in the Wnt/β-catenin pathway were evaluated through overexpression or knockdown of miR-320e under H2O2-induced oxidative stress. Wnt2-targeting siRNA was used to confirm the role of miR-320e in the Wnt2-mediated inhibition of the Wnt/β-catenin pathway. A retrospective analysis was conducted among patients with CVSD to assess the correlation between miR-320e expression and cognitive impairment and depression, which were quantified using the Montreal Cognitive Assessment (MoCA)/Executive Function Assessment (EFA) and the Hamilton Depression Scale (HAMD)/Beck Depression Inventory (BDI), respectively. Overall, these methods provided valuable insights into the potential role of exosomal miR-320e in the pathophysiology of CVSD and its potential clinical significance.

Research results

The results of the study indicate that exosomal miR-320e is downregulated in patients with CVSD. Exosomal miR-320e was found to inhibit the Wnt/β-catenin pathway in response to oxidative stress by targeting the 3' noncoding region of Wnt2. Uptake of exosomes carrying miR-320e could also target Wnt2 and inhibit the Wnt2/β-catenin pathway in endothelial cells. The study also found that elevated miR-320e expression may protect patients with CVSD from relatively severe cognitive impairment and depression, as it had a positive correlation with the MoCA/EFA and HAMD/BDI scores. These findings suggest that exosomal miR-320e may have a potentially protective role in CVSD progression and could be a novel therapeutic target for this complex neurodegenerative disorder. Overall, the results provide important insights into the pathophysiology of CVSD and highlight the importance of exosomal miRNAs in neurological diseases.

Research conclusions

The study found that exosomal miR-320e is downregulated in patients with CVSD and may play a crucial role in the progression of the disease. Exosomal miR-320e was found to inhibit the Wnt/β-catenin pathway by targeting the 3' noncoding region of Wnt2 in response to oxidative stress. The uptake of exosomes carrying miR-320e could also target Wnt2 and inhibit the Wnt2/β-catenin pathway in endothelial cells. Furthermore, elevated miR-320e expression was found to have a positive correlation with cognitive function and depression scores, suggesting it may protect patients from severe cognitive impairment and depression. The study provides new insights into the pathophysiology of CVSD and highlights the potential clinical significance of exosomal miRNAs in neurological diseases. These findings have implications for the development of novel therapeutic targets for CVSD and may provide hope for patients with this complex neurodegenerative disorder.

Research perspectives

The study provides valuable insights into the potential role of exosomal miR-320e in the pathophysiology of CVSD. Future research could investigate the use of exosomal miR-320e as a therapeutic target to prevent or delay the progression of CVSD. Further studies could also investigate the underlying mechanisms by which miR-320e regulates the Wnt/β-catenin pathway and how it affects cognitive function and depression. In addition, the use of animal models could provide further insight into the potential clinical significance of exosomal miRNAs in neurological diseases. Further research could also explore the potential diagnostic and prognostic value of miR-320e in patients with CVSD. Overall, the findings of this study pave the way for future research on the role of exosomal miRNAs in CVSD and other neurodegenerative disorders.