Li Xiao-Wan, Lu Yang-Yang, Zhang Shu-Yao, Sai Ning-Ning, Fan Yu-Yan, Cheng Yong, Liu Qing-Shan
Key Laboratory of Ethnomedicine for Ministry of Education, Center on Translational Neuroscience, Minzu University of China, Beijing, China.
Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
Front Pharmacol. 2022 Jun 22;13:926123. doi: 10.3389/fphar.2022.926123. eCollection 2022.
A sharp decline in neural regeneration in patients with Alzheimer's disease (AD) exacerbates the decline of cognition and memory. It is of great significance to screen for innovative drugs that promote endogenous neural regeneration. Cytisine N-methylene-(5,7,4'-trihydroxy)-isoflavone (LY01) is a new compound isolated from the Chinese herbal medicine with both isoflavone and alkaloid characteristic structures. Its pharmacological effects are worth studying. This study was designed to determine whether LY01 delays the cognitive and memory decline in the early stage of AD and whether this effect of LY01 is related to promoting neural regeneration. Eight-week-old 5×Familial Alzheimer's Disease (5×FAD) mice were used as disease models of early AD. Three doses of LY01 administered in two courses (2 and 5 weeks) of treatment were tested. Cognition, memory, and anxiety-like behaviors in mice were evaluated by the Morris water maze, fear conditioning, and open field experiments. Regeneration of neurons in the mouse hippocampus was observed using immunofluorescence staining. The effect of LY01 on cell regeneration was also demonstrated using a series of tests on primary cultured neurons, astrocytes, and neural stem cells (NSCs). In addition, flow cytometry and transcriptome sequencing were carried out to preliminarily explored the mechanisms. We found that LY01 reduced the decline of cognition and memory in the early stage of 5×FAD mice. This effect was related to the proliferation of astrocytes, the proliferation and migration of NSCs, and increases in the number of new cells and neural precursor cells in the dentate gyrus area of 5×FAD mice. This phenomenon could be observed both in 2-week-old female and 5-week-old male LY01-treated 5×FAD mice. The neuronal regeneration induced by LY01 was related to the regulation of the extracellular matrix and associated receptors, and effects on the S phase of the cell cycle. LY01 increases the proliferation of NSCs and astrocytes and the number of neural precursor cells in the hippocampus, resulting in neural regeneration in 5×FAD mice by acting on the extracellular matrix and associated receptors and regulating the S phase of the cell cycle. This provides a new idea for the early intervention and treatment of AD.
阿尔茨海默病（AD）患者神经再生的急剧下降加剧了认知和记忆的衰退。筛选促进内源性神经再生的创新药物具有重要意义。金雀花碱N-亚甲基-（5,7,4'-三羟基）-异黄酮（LY01）是从具有异黄酮和生物碱特征结构的中药中分离出的一种新化合物。其药理作用值得研究。本研究旨在确定LY01是否能延缓AD早期的认知和记忆衰退，以及LY01的这种作用是否与促进神经再生有关。将8周龄的5×家族性阿尔茨海默病（5×FAD）小鼠用作早期AD的疾病模型。测试了在两个疗程（2周和5周）治疗中给予的三种剂量的LY01。通过莫里斯水迷宫、恐惧条件反射和旷场实验评估小鼠的认知、记忆和焦虑样行为。使用免疫荧光染色观察小鼠海马体中神经元的再生。还通过对原代培养的神经元、星形胶质细胞和神经干细胞（NSCs）进行一系列测试来证明LY01对细胞再生的影响。此外，进行了流式细胞术和转录组测序以初步探索其机制。我们发现LY01减少了5×FAD小鼠早期的认知和记忆衰退。这种作用与星形胶质细胞的增殖、神经干细胞的增殖和迁移以及5×FAD小鼠齿状回区域新细胞和神经前体细胞数量的增加有关。在2周龄雌性和5周龄雄性LY01处理的5×FAD小鼠中均能观察到这种现象。LY01诱导的神经元再生与细胞外基质和相关受体的调节以及对细胞周期S期的影响有关。LY01通过作用于细胞外基质和相关受体并调节细胞周期的S期，增加了神经干细胞和星形胶质细胞的增殖以及海马体中神经前体细胞的数量，从而在5×FAD小鼠中实现神经再生。这为AD的早期干预和治疗提供了新思路。
