2′,3′-Dideoxycytidine, a DNA Polymerase-β Inhibitor, Reverses Memory Deficits in a Mouse Model of Alzheimer’s Disease

Article type: Research Article

Authors: Meng, Lanxia^{a; 1} | He, Mingyang^{a; 1} | Xiong, Min^a | Zhang, Xingyu^a | Nie, Shuke^a | Xiong, Jing^a | Hu, Dan^a | Zhang, Zhaohui^a | Mao, Ling^{b; *} | Zhang, Zhentao^{a; *}

Affiliations: [a] Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China | [b] Department of Neurology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China

Correspondence: [*] Correspondence to: Zhentao Zhang, Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China. E-mail: zhentao104@gmail.com and Ling Mao, Department of Neurology, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, China. E-mail: maoling13096@163.com.

Note: [1] These authors contributed equally to this work.

Abstract: The etiology and pathogenesis of Alzheimer’s disease (AD) are not fully understood. Thus, there are no drugs available that can provide a cure for it. We and others found that DNA polymerase-β (DNA pol-β) is required for neuronal death in several neurodegenerative models. In the present study, we tested the effect of a DNA pol-β inhibitor 2′,3′– Dideoxycytidine (DDC) in AD models both in vitro and in vivo. DDC protected primary neurons from amyloid-β (Aβ)-induced toxicity by inhibiting aberrant DNA replication mediated by DNA pol– β. Chronic oral administration of DDC alleviated Aβ deposition and memory deficits in the Tg2576 mouse model of AD. Moreover, DDC reversed synaptic loss in Tg2576 mice. These results suggest that DDC represents a novel therapeutic agent for the treatment of AD.

Keywords: 2′,3′– Dideoxycytidine, Alzheimer’s disease, DNA polymerase-β, synapse

DOI: 10.3233/JAD-180798

Journal: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 515-525, 2019