%0 Journal Article
%T Small interfering RNA delivery to the neurons near the amyloid plaques for improved treatment of Alzheimer£¿s disease
%A Dongyu Sheng
%A Jinxu Cao
%A Kang Qian
%A Liuchang Wang
%A Peng Yang
%A Pengzhen Wang
%A Qian Guo
%A Shuting Xu
%A Wei Lu
%A Xiaoyao Zheng
%A Xiaoying Pang
%A Xinguo Jiang
%J Archive of "Acta Pharmaceutica Sinica. B".
%D 2019
%R 10.1016/j.apsb.2018.12.010
%X 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¨Cbrain barrier (BBB) penetration and QSH peptide for ¦Â-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 ¦Â-site amyloid precursor protein-cleaving enzyme 1 (BACE1), the rate-limiting enzyme of A¦Â production, as the therapeutic siRNA of AD. The nanocomplexes exhibited high distribution in the A¦Â 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 A¦Â 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
%K siRNA delivery
%K Neurons
%K Amyloid plaques
%K BACE1 gene
%K Alzheimer£¿s disease
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543096/