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

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

来源：Molecular Therapy-Nucleic Acids, 2022, 28: 114-123.

DOI：10.1016/j.omtn.2022.02.018

• ALZHEIMERS-DISEASE
• MULTIFUNCTIONAL CHOLINESTERASE
• BIFUNCTIONAL APTAMER
• TRANSFERRIN RECEPTOR
• CHOLINERGIC SYSTEM
• CANCER
• TAU

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 5xFAD 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 5xFAD mice in the Morris water maze. Moreover, the mechanism of aptamer Ob2 in 5xFAD mice may be associated with its inhibition of AChE activity, alleviation of the levels of A beta by lowering the expression of beta-secretase (BACE1), and activation of astrocytes in the brains of 5xFAD mice. These results indicate that aptamer Ob2 exhibits potential as an effective AChEI for the treatment of AD.

• 单位
  1; 南方医科大学; 5