Liang Zhiman, Li Xin, Luo Xiaoting, Luo Hongjie, Chen Yajun, Cai Mingliang, Zhong Xinxin, Fang Yingying, Guo Ting, Shi Yusheng, Zhang Xingmei
Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
Department of Pathology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou 510900, China.
Mol Ther Nucleic Acids. 2022 Feb 28;28:114-123. doi: 10.1016/j.omtn.2022.02.018. eCollection 2022 Jun 14.
Loss of cerebral cholinergic neurons and decreased levels of acetylcholine (ACh) are considered to be major factors causing cognitive dysfunction in Alzheimer's disease (AD). Abnormally elevated levels of acetylcholinesterase (AChE) resulting in decreased levels of ACh are common in AD patients; thus, AChE inhibitors (AChEIs) are widely used for the treatment of AD. In our previous work, we acquired DNA aptamers Ob1, Ob2, and Ob3 against human brain AChE from systematic evolution of ligands by exponential enrichment (SELEX). In this study, we investigated the effect of these aptamers on learning and memory abilities, as well as the underlying mechanism in a 5×FAD transgenic AD mouse model. Here, we showed that only aptamer Ob2 exhibits a good inhibitory effect on both mouse and human AChE activity. In addition, chronic treatment with aptamer Ob2 significantly improved cognitive ability of 5×FAD mice in the Morris water maze. Moreover, the mechanism of aptamer Ob2 in 5×FAD mice may be associated with its inhibition of AChE activity, alleviation of the levels of Aβ by lowering the expression of β-secretase (BACE1), and activation of astrocytes in the brains of 5×FAD mice. These results indicate that aptamer Ob2 exhibits potential as an effective AChEI for the treatment of AD.
大脑胆碱能神经元的丧失和乙酰胆碱（ACh）水平的降低被认为是导致阿尔茨海默病（AD）认知功能障碍的主要因素。乙酰胆碱酯酶（AChE）水平异常升高导致ACh水平降低在AD患者中很常见；因此，AChE抑制剂（AChEIs）被广泛用于治疗AD。在我们之前的工作中，我们通过指数富集配体系统进化技术（SELEX）获得了针对人脑AChE的DNA适配体Ob1、Ob2和Ob3。在本研究中，我们在5×FAD转基因AD小鼠模型中研究了这些适配体对学习和记忆能力的影响及其潜在机制。在此，我们表明只有适配体Ob2对小鼠和人AChE活性均表现出良好的抑制作用。此外，用适配体Ob2进行慢性治疗可显著改善5×FAD小鼠在莫里斯水迷宫中的认知能力。而且，适配体Ob2在5×FAD小鼠中的作用机制可能与其抑制AChE活性、通过降低β-分泌酶（BACE1）的表达减轻Aβ水平以及激活5×FAD小鼠大脑中的星形胶质细胞有关。这些结果表明，适配体Ob2作为一种有效的AChEI用于治疗AD具有潜力。
