Zheng Rui, Zhang Zhong-Hao, Chen Chen, Chen Yao, Jia Shi-Zheng, Liu Qiong, Ni Jia-Zuan, Song Guo-Li
Shenzhen Key Laboratory of Marine Bioresources and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China.
Shenzhen Key Laboratory of Marine Bioresources and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China.
Biochem Biophys Res Commun. 2017 Mar 25;485(1):6-15. doi: 10.1016/j.bbrc.2017.01.069. Epub 2017 Jan 19.
The maintenance of neural system integrity and function is the ultimate goal for the treatment of neurodegenerative disease such as Alzheimer's disease (AD). Neurogenesis plays an integral role in the maintenance of neural and cognitive functions, and its dysfunction is regarded as a major cause of cognitive impairment in AD. Moreover, the induction of neurogenesis by targeting endogenous neural stem cells (NSCs) is considered as one of the most promising treatment strategies. Our previous studies demonstrated that selenomethionine (Se-Met) was able to reduce β-amyloid peptide (Aβ) deposition, decrease Tau protein hyperphosphorylation and markedly improve cognitive functions in triple transgenic (3xTg) AD mice. In this study, we reported that the therapeutic effect of Se-Met on AD could also be due to neurogenesis modulation. By using the cultured hippocampal NSCs from 3xTg AD mice, we discovered that Se-Met (1-10 μM) with low concentration could promote NSC proliferation, while the one with a high concentration (50,100 μM) inhibiting proliferation. In subsequent studies, we also found that Se-Met activated the signaling pathway of PI3K/Akt, and thereby inhibited the GSK3β activity, which would further activated the β-catenin/Cyclin-D signaling pathway and promote NSC proliferation. Besides, after the induction of Se-Met, the number of neurons differentiated from NSCs significantly increased, and the number of astrocytes decreased. After a 90-day treatment with Se-Met (6 μg/mL), the number of hippocampal neurons in 4-month-old AD mice increased significantly, while the one of astrocyte saw a sharp drop. Thus, Se-Met treatment promoted NSCs differentiation into neurons, and subsequently repaired damaged neural systems in AD mice. Being consistent with our in vitro studies, Se-Met acts through the PI3K-Akt- GSK3β-Wnt signaling pathway in vivo. This study provides an unparalleled evidence that selenium (Se) compounds are, to some extent, effective in promoting neurogenesis, and therefore we propose a novel mechanism for Se-Met treatment in AD.
维持神经系统的完整性和功能是治疗诸如阿尔茨海默病（AD）等神经退行性疾病的最终目标。神经发生在维持神经和认知功能中起着不可或缺的作用，其功能障碍被认为是AD认知障碍的主要原因之一。此外，通过靶向内源性神经干细胞（NSCs）诱导神经发生被认为是最有前景的治疗策略之一。我们之前的研究表明，硒代蛋氨酸（Se-Met）能够减少β-淀粉样肽（Aβ）沉积，降低Tau蛋白过度磷酸化，并显著改善三转基因（3xTg）AD小鼠的认知功能。在本研究中，我们报道Se-Met对AD的治疗作用也可能归因于对神经发生的调节。通过使用来自3xTg AD小鼠的培养海马神经干细胞，我们发现低浓度的Se-Met（1-10μM）可促进神经干细胞增殖，而高浓度（50、100μM）的Se-Met则抑制增殖。在后续研究中，我们还发现Se-Met激活了PI3K/Akt信号通路，从而抑制了GSK3β活性，这将进一步激活β-连环蛋白/Cyclin-D信号通路并促进神经干细胞增殖。此外，在诱导Se-Met后，从神经干细胞分化而来的神经元数量显著增加，星形胶质细胞数量减少。在用Se-Met（6μg/mL）治疗90天后，4月龄AD小鼠海马神经元数量显著增加，而星形胶质细胞数量则急剧下降。因此，Se-Met治疗促进了神经干细胞向神经元的分化，并随后修复了AD小鼠受损的神经系统。与我们的体外研究一致，Se-Met在体内通过PI3K-Akt-GSK3β-Wnt信号通路发挥作用。本研究提供了无可比拟的证据，表明硒（Se）化合物在一定程度上对促进神经发生有效，因此我们提出了Se-Met治疗AD的新机制。
