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. 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 RVG-conjugated 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 IL-6, but the changes of anti-inflammatory factors IL-10 and IL-13 were not obvious. However, administration of MSC-RVG-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. 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.

中文翻译：

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来自间充质干细胞的 RVG 修饰的外泌体通过调节阿尔茨海默病小鼠模型中的炎症反应来挽救记忆缺陷

外泌体是脂质双层封闭的纳米级囊泡，可转移功能性细胞蛋白、mRNA 和 miRNA。间充质干细胞 (MSCs) 衍生的外泌体已被证明可预防阿尔茨海默病 (AD) 动物模型中的记忆缺陷。然而，除了大脑中的目标区域外，静脉注射的外泌体可以在其他器官中被大量追踪。在这里，我们建议使用中枢神经系统特异性狂犬病病毒糖蛋白 (RVG) 肽将静脉输注的源自 MSCs (MSC-Exo) 的外泌体靶向转基因 APP/PS1 小鼠的大脑。MSC-Exo 通过 DOPE-NHS 接头与 RVG 结合。RVG 标记的 MSC-Exo 在静脉内给药后表现出对皮质和海马体的靶向性提高。与施用 MSC-Exo 的组相比，在给予RVG结合MSC-Exo（MSC-RVG-Exo）的组中，斑块沉积和Aβ水平急剧下降，星形胶质细胞的活化明显降低。根据 Morris 水迷宫试验，源自 MSCs 的大脑靶向外泌体优于未修饰的外泌体，以改善 APP/PS1 小鼠的认知功能。此外，虽然静脉注射MSC-Exo降低了促炎介质TNF-α、IL-β和IL-6的表达，但抗炎因子IL-10和IL-13的变化并不明显。然而，MSC-RVG-Exo 的给药显着降低了 TNF-α、IL-β 和 IL-6 的水平，同时显着提高了 IL-10、IL-4 和 IL-13 的水平。总之，我们的结果证明了一种增加外泌体递送以治疗 AD 的新方法。