Ying Xie,1,* Tongxuan Ouyang,1,* Anli Xu,1 Qinglai Bian,1 Biran Zhu,1,2 Min Zhao1,2 

1School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, 430065, People’s Republic of China; 2Hubei Shizhen Laboratory, Wuhan, 430061, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Min Zhao; Biran Zhu, School of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road, Wuhan, Hubei Province, People’s Republic of China, 430065, Tel +86 13437155626, Email zmin13@hbucm.edu.cn; zhubir@hotmail.com

Background: Adult hippocampal neurogenesis plays a beneficial role in the treatment of depression. The precise mechanism by which let-7e-5p functions as a potential marker for depression remains unclear. Quercetin, a flavonoid compound, exhibits antidepressant effects; however, further investigation is needed to elucidate its regulatory effect and mechanism on hippocampal neurogenesis.
Methods: Chronic unpredictable mild stress (CUMS) was employed to induce depressive-like signaling and cognitive impairment in mice, while quercetin was administered via oral gavage. The symptoms of the mice were evaluated using various signaling methods. The expression levels of microglia, neural stem cells, and let-7e-5p in the dentate gyrus (DG) area of hippocampus were assessed using pathological observation methods. The expression levels of let-7e-5p and the Wnt1/β-catenin signaling pathways in the hippocampal DG of mice were assessed using qRT-PCR and Western blotting, respectively. The exosomes from peripheral blood were isolated and identified, followed by the detection of expression levels for microglia markers CD11b and TMEM119. We isolated hippocampal neural stem cells (NSCs) and co-cultured them with exosomes secreted by BV2 cells under LPS stimulation to observe the proliferation of NSCs and the generation of new neurons. The targeting relationship between let-7e-5p and Wnt1 was ultimately confirmed through the utilization of a dual luciferase reporter assay.
Results: (1) Quercetin ameliorated depression-like behaviors in mice induced by CUMS and restored neurogenesis in the DG region of the hippocampus. (2) Quercetin suppressed the secretion of microglia-derived exosomes carrying let-7e-5p in the DG, which exerted effects on NSC. (3) let-7e-5p regulates depression-related neurogenesis through targeting the Wnt1/β-catenin signaling pathway.
Conclusion: The inhibitory effect of let-7e-5p in microglial exosomes on depression-associated neurogenesis is mediated through the blockade of the Wnt1/β-catenin signaling pathway, which can be effectively reversed by Quercetin treatment.

Keywords: depression, neurogenesis, quercetin, microglia, exosome, let-7e-5p, Wnt1/β-catenin