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MSC-Derived Extracellular Vesicles Alleviate NLRP3/GSDMD-Mediated Neuroinflammation in Mouse Model of Sporadic Alzheimer’s Disease

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Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease, with sporadic form being the predominant type. Neuroinflammation plays a critical role in accelerating pathogenic processes in AD. Mesenchymal stem cell (MSC)–derived small extracellular vesicles (MSC-sEVs) regulate inflammatory responses and show great promise for treating AD. Induced pluripotent stem cell (iPSC)–derived MSCs are similar to MSCs and exhibit low immunogenicity and heterogeneity, making them promising cell sources for clinical applications. This study examined the anti-inflammatory effects of MSC-sEVs in a streptozotocin-induced sporadic mouse model of AD (sAD). The intracisternal administration of iPSC-MSC-sEVs alleviated NLRP3/GSDMD-mediated neuroinflammation, decreased amyloid deposition and neuronal apoptosis, and mitigated cognitive dysfunction. Furthermore, it explored the role of miR-223-3p in the iPSC-MSC-sEVs-mediated anti-inflammatory effects in vitro. miR-223-3p directly targeted NLRP3, whereas inhibiting miR-223-3p almost completely reversed the suppression of NLRP3 by MSC-sEVs, suggesting that miR-223-3p may, at least partially, account for MSC-sEVs-mediated anti-inflammation. Results obtained suggest that intracisternal administration of iPSC-MSC-sEVs can reduce cognitive impairment by inhibiting NLRP3/GSDMD neuroinflammation in a sAD mouse model. Therefore, the present study provides a proof-of-principle for applying iPSC-MSC-sEVs to target neuroinflammation in sAD.

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Data availability

The data that support the findings of this study are available on request from the corresponding author.

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This study was supported by grants from the National Key R&D Program of China (2022YFA1104900), the National Natural Science Foundation of China (No. 82271266, No. 82071255, No. 81873751, No. 82271144, No. 81970863), Guangdong Basic and Applied Basic Research Foundation (No. 2021B1515120062), the Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases (2020B1212060017), Guangdong Provincial Clinical Research Center for Neurological Diseases (2020B1111170002), Southern China International Joint Research Center for Early Intervention and Functional Rehabilitation of Neurological Diseases (2015B050501003 and 2020A0505020004), Guangdong Provincial Engineering Center for Major Neurological Disease Treatment, Guangdong Provincial Translational Medicine Innovation Platform for Diagnosis and Treatment of Major Neurological Disease, Guangzhou Clinical Research and Translational Center for Major Neurological Diseases (201604020010), Young Talent Recruitment Project of Guangdong (2019QN01Y139), The Fundamental Research Funds for the Central Universities, Sun Yat-sen University (22ykqb07), Guangdong Basic and Applied Basic Research Foundation (2021B1515120062), and Guangzhou Key R&D Program (2023B03J1233, 20220600003).

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Author notes

  1. Lishan Lin, Longxin Huang, and Sen Huang contributed equally to this work

Authors and Affiliations

  1. Department of Neurology, The First Affiliated Hospital, Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases; National Key Clinical Department and Key Discipline of Neurology, Sun Yat-Sen University, Guangzhou, 510080, China

    Lishan Lin, Sen Huang, Weineng Chen, Fengjuan Su, Kang Yuan, Qiuhong Jiang & Zhong Pei

  2. Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China

    Longxin Huang, Xiaoqing Liu, Changu Li & Qingling Fu

  3. Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China

    Longxin Huang, Xiaoqing Liu, Changu Li & Qingling Fu

  4. Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China

    Heng Huang

  5. Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Institute of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, 510080, China

    Li Chi

  6. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA

    Wanli W. Smith

Authors
  1. Lishan Lin
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  2. Longxin Huang
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  3. Sen Huang
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  4. Weineng Chen
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  6. Li Chi
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  7. Fengjuan Su
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  11. Changu Li
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  13. Qingling Fu
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  14. Zhong Pei
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by LL, LH, SH, WC, HH, LC, FS, XL, KY, QJ, and CL. The first draft of the manuscript was written by LL, WWS, QF, and ZP. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Qingling Fu or Zhong Pei.

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Ethical Approval

Authors obtained ethics approval form the Sun Yat-sen University. Care of the animals was in accordance with the Guide for the Care and Use of Laboratory Animals of Sun Yat-sen University (Guangzhou, China).

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The authors declare no competing interests.

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Lin, L., Huang, L., Huang, S. et al. MSC-Derived Extracellular Vesicles Alleviate NLRP3/GSDMD-Mediated Neuroinflammation in Mouse Model of Sporadic Alzheimer’s Disease. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-03914-1

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