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
Abstract
BACKGROUND

Exosomal miRNAs play crucial roles in many central nervous system diseases. Cerebral small vessel disease (CVSD) is a small vessel disease that is affected by various factors. This study aimed to investigate the role of exosomal miR-320e in the Wnt/β-catenin pathway stimulated by oxidative stress and assess its clinical correlation with psychiatric symptoms in patients with CVSD.

AIM

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.

METHODS

Differentially expressed exosomal miRNAs were filtered by sequencing plasma exosomes from patients with CVSD and healthy controls. Bioinformatics and dual luciferase analyses were used to confirm the binding of miR-320e to Wnt2, and the mRNA and protein levels of downstream components in the Wnt/β-catenin pathway were evaluated when overexpressed or with knockdown of miR-320e under H2O2-induced oxidative stress. In addition, 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 confirm the correlation between miR-320e expression and the severity of 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.

RESULTS

High-throughput sequencing revealed that exosomal miR-320e was downregulated in patients with CVSD. Bioinformatics analysis and dual-luciferase reporter gene experiments showed that exosomal miR-320e inhibited the Wnt/β-catenin pathway in response to oxidative stress by targeting the 3' noncoding region of Wnt2. Uptake of exosomes carrying miR-320e into endothelial cells could also target Wnt2 and inhibit the Wnt2/β-catenin pathway. Elevated miR-320e expression may protect patients with CVSD from relatively severe cognitive impairment and depression, as it was found to have a positive correlation with the MoCA/EFA and HAMD/BDI scores.

CONCLUSION

Our results suggest that exosomal miR-320e suppresses the Wnt/β-catenin pathway and may play a protective role in CVSD progression.

Keywords: Exosome; Cerebral small vessel disease; miRNA-320e; Wnt2; Wnt/β-catenin pathway; Depressed

Core Tip: Exosomal miR-320e is downregulated in patients with cerebral small vessel disease (CVSD), and it inhibits the Wnt/β-catenin pathway by targeting Wnt2 in response to oxidative stress. Uptake of exosomes carrying miR-320e can also target Wnt2 and inhibit the Wnt2/β-catenin pathway. Elevated miR-320e expression may protect patients with CVSD from severe cognitive impairment and depression, as it correlates positively with Montreal Cognitive Assessment/Executive Function Assessment and Hamilton Depression Scale/Beck Depression Inventory scores. Therefore, exosomal miR-320e may play a protective role in CVSD progression by suppressing the Wnt/β-catenin pathway, indicating its potential as a therapeutic target for CVSD.