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Exosomes Isolated From Human Umbilical Cord Mesenchymal Stem Cells Alleviate Neuroinflammation and Reduce Amyloid-Beta Deposition by Modulating Microglial Activation in Alzheimer’s Disease

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Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized by excessive accumulation of the amyloid-β peptide (Aβ) in the brain, which has been considered to mediate the neuroinflammation process. Microglial activation is the main component of neuroimmunoregulation. In recent years, exosomes isolated from human umbilical cord mesenchymal stem cells (hucMSC-exosomes) have been demonstrated to mimic the therapeutic effects of hucMSCs in many inflammation-related diseases. In this study, exosomes from the supernatant of hucMSCs were injected into AD mouse models. We observed that hucMSC-exosomes injection could repair cognitive disfunctions and help to clear Aβ deposition in these mice. Moreover, we found that hucMSC-exosomes injection could modulate the activation of microglia in brains of the mice to alleviated neuroinflammation. The levels of pro-inflammatory cytokines in peripheral blood and brains of mice were increased and the levels of anti-inflammatory cytokines were decreased. We also treated BV2 cells with hucMSC-exosomes in culture medium. HucMSC-exosomes also had inflammatory regulating effects to alternatively activate microglia and modulate the levels of inflammatory cytokines in vitro.

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Abbreviations

AD:

Alzheimer disease

Aβ:

Amyloid β- peptides

hucMSC-exosomes:

Exosomes isolated from human umbilical cord mesenchymal stem cells

CNS:

Central nervous system

BBB:

Blood–brain barrier

PBS:

Phosphate-buffered saline

RC:

Reagent of the control group

MWM:

Morris water-maze

PB:

Peripheral blood

TGF-β:

Transforming growth factor-β

IL-10:

Interleukin-10

TNF-α:

Tumor necrosis factor-α

IL-1β:

Interleukin-1β

ELISA:

Enzyme-linked immunosorbent assay

NEP:

Neprilysin

IDE:

Insulin-degrading enzyme

YM-1:

Chitinase 3-like 3

Arg-1:

Arginase-1

CD163:

Haptoglobin/hemoglobin scavenger receptor

FIZZ1:

Found in inflammatory zone 1

MRC1:

Mannose receptors C type 1

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Funding

This study was supported by National Natural Science Foundation of China (Grant Nos. 81401052, 81571052), The Special fund for basic research and business funds of Chinese Centre Universities (Grant No. 2018BTS01), Science and Technology Development Plan Project of Shandong Province (Grant Nos. 2017GSF218036, 2017GSF218046), The Fundamental Research Funds of Shandong University (Grant No. 2016JC022), Youth Talent Fund of the 2nd Hospital of Shandong University (Grant No. 2018YT09) and Focus on research and development projects in Shandong province (Grant No. 2015GSF118056).

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Authors and Affiliations

  1. Medicine School, Shandong University, Jinan, 250012, China

    Mao Ding & Yang Shen

  2. Department of Neurology Medicine, Second Hospital of Shandong University, Jinan, 250033, China

    Ping Wang, Zhaohong Xie, Shunliang Xu, ZhengYu Zhu, Yun Wang, Dewei Wang, Linlin Xu, JianZhong Bi & Hui Yang

  3. Department of Neurology Medicine, Shandong Provincial Third Hospital, Jinan, 250031, China

    Yongtao Lyu

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  1. Mao Ding
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  2. Yang Shen
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  9. Dewei Wang
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  11. JianZhong Bi
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Contributions

MD designed and performed the experiments and wrote the manuscript. YS, ZHX participated in designing the experiments. PW, SLX, and ZYZ provided assistance for data analysis, mouse-injection experiments, and ELISA assay, respectively. YW, YTL, LLX and DWW were responsible for mouse-behavior observation. HY and JZB participated in designing the experiments and drafting the manuscript. All authors read and approved the manuscript for publication.

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Correspondence to JianZhong Bi or Hui Yang.

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The authors declare that they have no conflict of interests.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of Shandong University and the ethical committee of the Second Hospital of Shandong University and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All applicable Shandong University and the ethical committee of the Second Hospital of Shandong University guidelines for the care and use of animals were followed.

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Informed consent was obtained from all individual participants included in the study.

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Ding, M., Shen, Y., Wang, P. et al. Exosomes Isolated From Human Umbilical Cord Mesenchymal Stem Cells Alleviate Neuroinflammation and Reduce Amyloid-Beta Deposition by Modulating Microglial Activation in Alzheimer’s Disease. Neurochem Res 43, 2165–2177 (2018). https://doi.org/10.1007/s11064-018-2641-5

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