Small interfering RNA delivery to the neurons near the amyloid plaques for improved treatment of Alzheimer׳s disease
| Autor: | Xinguo Jiang, Dongyu Sheng, Kang Qian, Jinxu Cao, Wei Lu, Qian Guo, Liuchang Wang, Pengzhen Wang, Xiaoyao Zheng, Xiaoying Pang, Qizhi Zhang, Shuting Xu, Peng Yang |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Genetically modified mouse
Original article 0303 health sciences Small interfering RNA Amyloid biology business.industry Genetic enhancement lcsh:RM1-950 Gene delivery 03 medical and health sciences lcsh:Therapeutics. Pharmacology 0302 clinical medicine medicine.anatomical_structure 030220 oncology & carcinogenesis mental disorders Systemic administration Synaptophysin biology.protein Cancer research Medicine Neuron General Pharmacology Toxicology and Pharmaceutics business 030304 developmental biology |
| Zdroj: | Acta Pharmaceutica Sinica B, Vol 9, Iss 3, Pp 590-603 (2019) |
| ISSN: | 2211-3835 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|