Original articles
Qian Guo, Xiaoyao Zheng, Peng Yang, Xiaoying Pang, Kang Qian, Pengzhen Wang, Shuting Xu, Dongyu Sheng, Liuchang Wang, Jinxu Cao, Wei Lu, Qizhi Zhang, Xinguo Jiang. Small interfering RNA delivery to the neurons near the amyloid plaques for improved treatment of Alzheimer's disease[J]. Acta Pharmaceutica Sinica B, 2019, 9(3): 590-603

Small interfering RNA delivery to the neurons near the amyloid plaques for improved treatment of Alzheimer's disease
Qian Guo, Xiaoyao Zheng, Peng Yang, Xiaoying Pang, Kang Qian, Pengzhen Wang, Shuting Xu, Dongyu Sheng, Liuchang Wang, Jinxu Cao, Wei Lu, Qizhi Zhang, Xinguo Jiang
Key Laboratory of Smart Drug Delivery, Ministry of Education, & State Key Laboratory of Molecular Engineering of Polymers, School of Pharmacy, Fudan University, Shanghai 201203, China
Abstract:
Gene therapy represents a promising treatment for the Alzheimer's disease (AD). However, gene delivery specific to brain lesions through systemic administration remains big challenge. In our previous work, we have developed an siRNA nanocomplex able to be specifically delivered to the amyloid plaques through surface modification with both CGN peptide for the blood-brain barrier (BBB) penetration and QSH peptide for β-amyloid binding. But, whether the as-designed nanocomplex could indeed improve the gene accumulation in the impaired neuron cells and ameliorate AD-associated symptoms remains further study. Herein, we prepared the nanocomplexes with an siRNA against β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), the rate-limiting enzyme of Aβ production, as the therapeutic siRNA of AD. The nanocomplexes exhibited high distribution in the Aβ deposits-enriched hippocampus, especially in the neurons near the amyloid plaques after intravenous administration. In APP/PS1 transgenic mice, the nanocomplexes down-regulated BACE1 in both mRNA and protein levels, as well as Aβ and amyloid plaques to the level of wild-type mice. Moreover, the nanocomplexes significantly increased the level of synaptophysin and rescued memory loss of the AD transgenic mice without hematological or histological toxicity. Taken together, this work presented direct evidences that the design of precise gene delivery to the AD lesions markedly improves the therapeutic outcome.
Key words:    siRNA delivery    Neurons    Amyloid plaques    BACE1 gene    Alzheimer's disease   
Received: 2018-09-12     Revised:
DOI: 10.1016/j.apsb.2018.12.010
Funds: This work was supported by the National Natural Science Foundation of China (Nos. 81473150 and 81273461), Major Program of National Natural Science Foundation of China (No. 81690263) and the National Basic Research Program of China (No. 2013CB932500).
Corresponding author: Wei Lu, Qizhi Zhang     Email:wlu@fudan.edu.cn;qzzhang@fudan.edu.cn
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Authors
Qian Guo
Xiaoyao Zheng
Peng Yang
Xiaoying Pang
Kang Qian
Pengzhen Wang
Shuting Xu
Dongyu Sheng
Liuchang Wang
Jinxu Cao
Wei Lu
Qizhi Zhang
Xinguo Jiang

References:
1. Prince M, Wimo A, Guerchet M, Ali G, Wu Y, Prina M. World Alzheimer report 2015. The global impact of dementia. An analysis of prevalence, incidence, cost and trends. London:Alzheimer's Disease International; 2015 Available form: