Xie Ying, Ouyang Tongxuan, Xu Anli, Bian Qinglai, Zhu Biran, Zhao Min
School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, 430065, People's Republic of China.
Hubei Shizhen Laboratory, Wuhan, 430061, People's Republic of China.
Drug Des Devel Ther. 2025 Mar 24;19:2189-2203. doi: 10.2147/DDDT.S493779. eCollection 2025.
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.
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.
(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.
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.
成年海马神经发生在抑郁症治疗中发挥有益作用。let-7e-5p作为抑郁症潜在标志物发挥作用的确切机制尚不清楚。槲皮素是一种黄酮类化合物，具有抗抑郁作用；然而，需要进一步研究以阐明其对海马神经发生的调节作用和机制。
采用慢性不可预测轻度应激（CUMS）诱导小鼠抑郁样信号和认知障碍，同时通过灌胃给予槲皮素。使用各种信号方法评估小鼠的症状。使用病理观察方法评估海马齿状回（DG）区域中小胶质细胞、神经干细胞和let-7e-5p的表达水平。分别使用qRT-PCR和蛋白质免疫印迹法评估小鼠海马DG中let-7e-5p的表达水平和Wnt1/β-连环蛋白信号通路。分离并鉴定外周血中的外泌体，随后检测小胶质细胞标志物CD11b和TMEM119的表达水平。我们分离海马神经干细胞（NSCs），并将其与LPS刺激下BV2细胞分泌的外泌体共培养，以观察NSCs的增殖和新神经元的生成。最终通过双荧光素酶报告基因检测确定let-7e-5p与Wnt1之间的靶向关系。
（1）槲皮素改善了CUMS诱导的小鼠抑郁样行为，并恢复了海马DG区域的神经发生。（2）槲皮素抑制了DG中携带let-7e-5p的小胶质细胞来源外泌体的分泌，这些外泌体对神经干细胞产生影响。（3）let-7e-5p通过靶向Wnt1/β-连环蛋白信号通路调节与抑郁相关的神经发生。
小胶质细胞外泌体中let-7e-5p对抑郁相关神经发生的抑制作用是通过阻断Wnt1/β-连环蛋白信号通路介导的，槲皮素治疗可有效逆转这种作用。
