RVG-modified exosomes derived from mesenchymal stem cells rescue memory deficits by regulating inflammatory responses in
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RESEARCH
Open Access
RVG-modified exosomes derived from mesenchymal stem cells rescue memory deficits by regulating inflammatory responses in a mouse model of Alzheimer’s disease Guo-hong Cui1†, Hai-dong Guo2†, Han Li2†, Yu Zhai1, Zhang-bin Gong3, Jing Wu1, Jian-sheng Liu1, You-rong Dong1, Shuang-xing Hou4* and Jian-ren Liu1*
Abstract Background: Exosomes are lipid-bilayer enclosed nano-sized vesicles that transfer functional cellular proteins, mRNA and miRNAs. Mesenchymal stem cells (MSCs) derived exosomes have been demonstrated to prevent memory deficits in the animal model of Alzheimer’s disease (AD). However, the intravenously injected exosomes could be abundantly tracked in other organs except for the targeted regions in the brain. Here, we proposed the use of central nervous system-specific rabies viral glycoprotein (RVG) peptide to target intravenously-infused exosomes derived from MSCs (MSC-Exo) to the brain of transgenic APP/PS1 mice. MSC-Exo were conjugated with RVG through a DOPE-NHS linker. Results: RVG-tagged MSC-Exo exhibited improved targeting to the cortex and hippocampus after being administered intravenously. Compared with the group administered MSC-Exo, in the group administered RVGconjugated MSC-Exo (MSC-RVG-Exo) plaque deposition and Aβ levels were sharply decreased and activation of astrocytes was obviously reduced. The brain targeted exosomes derived from MSCs was better than unmodified exosomes to improve cognitive function in APP/PS1 mice according to Morris water maze test. Additionally, although MSC-Exo injected intravenously reduced the expression of pro-inflammatory mediators TNF-α, IL-β, and IL6, but the changes of anti-inflammatory factors IL-10 and IL-13 were not obvious. However, administration of MSCRVG-Exo significantly reduced the levels of TNF-α, IL-β, and IL-6 while significantly raised the levels of IL-10, IL-4 and IL-13. Conclusions: Taken together, our results demonstrated a novel method for increasing delivery of exosomes for treatment of AD. By targeting exosomes to the cortex and hippocampus of AD mouse, there was a significant improvement in learning and memory capabilities with reduced plaque deposition and Aβ levels, and normalized levels of inflammatory cytokines. Keywords: Alzheimer’s disease, Exosomes, Targeting, Mesenchymal stem cells, Inflammatory cytokine
* Correspondence: [email protected]; [email protected] † Guo-hong Cui, Hai-dong Guo and Han Li contributed equally to this work. 4 Department of Neurology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China 1 Department of Neurology, Shanghai No. 9 People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, p
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