2. Academic Validation
  3. RVG-modified exosomes derived from mesenchymal stem cells rescue memory deficits by regulating inflammatory responses in a mouse model of Alzheimer's disease

RVG-modified exosomes derived from mesenchymal stem cells rescue memory deficits by regulating inflammatory responses in a mouse model of Alzheimer's disease

  • Immun Ageing. 2019 May 13;16:10. doi: 10.1186/s12979-019-0150-2.
Guo-Hong Cui # 1,  Hai-Dong Guo # 2,  Han Li # 2,  Yu Zhai 1,  Zhang-Bin Gong 3,  Jing Wu 1,  Jian-Sheng Liu 1,  You-Rong Dong 1,  Shuang-Xing Hou 4,  Jian-Ren Liu 1
Affiliations

Affiliations

  • 1 1Department of Neurology, Shanghai No. 9 People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200011 China.
  • 2 2Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203 China.
  • 3 3Department of Biochemistry, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203 China.
  • 4 4Department of Neurology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399 China.
  • # Contributed equally.
PMID: 31114624 DOI: 10.1186/s12979-019-0150-2
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 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.

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; Inflammatory cytokine; Mesenchymal stem cells; Targeting.

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