The Aptamer Ob2, a novel AChE inhibitor, restores cognitive deficits and alleviates amyloidogenesis in 5×FAD transgenic mice

Zhiman Liang; Xin Li; Xiaoting Luo; Hongjie Luo; Yajun Chen; Mingliang Cai; Xinxin Zhong; Yingying Fang; Ting Guo; Yusheng Shi; Xingmei Zhang

doi:10.1016/j.omtn.2022.02.018

The Aptamer Ob2, a novel AChE inhibitor, restores cognitive deficits and alleviates amyloidogenesis in 5×FAD transgenic mice

Mol Ther Nucleic Acids. 2022 Feb 28:28:114-123. doi: 10.1016/j.omtn.2022.02.018. eCollection 2022 Jun 14.

Authors

Zhiman Liang^{1

2}, Xin Li¹, Xiaoting Luo³, Hongjie Luo⁴, Yajun Chen⁴, Mingliang Cai³, Xinxin Zhong¹, Yingying Fang¹, Ting Guo¹, Yusheng Shi^{3

5}, Xingmei Zhang¹

Affiliations

¹ 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.
² Department of Pathology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou 510900, China.
³ Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
⁴ The First Affiliated Hospital, Southern Medical University, Guangzhou 510515, China.
⁵ Department of Radiation Oncology, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai 519000, China.

Abstract

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.

Keywords: 5×FAD mice; AChE inhibitor; Alzheimer’s disease; MT: Oligonucleotides: Therapies and Applications; acetylcholinesterase; aptamer.