Engineered mesenchymal stem cell-derived extracellular vesicles overexpressing miR-146a alleviate neuroinflammation in Alzheimer's disease.
6 affiliations
- 1The Second Affiliated Hospital, University of South China, Hengyang, Hunan Province, China
- 2Division of Gastroenterology, Institute of Digestive Disease, the Affiliated Qingyuan Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong Province, China
- 3Department of Physiology & Key Laboratory of Hunan Province for Major Brain Diseases, Hengyang Medical School, University of South China, Hengyang, Hunan Province, China
- 4The First Affiliated Hospital, Institute of Anesthesiology, University of South China, Hengyang, Hunan Province, China
- 5Guangdong-Hong Kong-Macau Institute of Central Nervous System Regeneration, Key Laboratory of Central Nervous System Regeneration, Ministry of Education, Jinan University, Guangzhou, Guangdong Province, China
- 6Department of Pathology, Beihua University, Jilin, Jilin Province, China
Abstract
Alzheimer’s disease is an inflammatory neurodegenerative disease for which no effective clinical treatment currently exists. We have previously reported that mesenchymal stem cell–derived extracellular vesicles delay retinal degeneration by exerting anti-inflammatory effects though the miR-146a–nuclear receptor subfamily 4 group A member 3 axis; however, it remains unclear how NR4A3 drives inflammation. Herein, we engineered mesenchymal stem cell–derived extracellular vesicles overexpressing miR-146a to explore their possible neuroprotective effects and the underlying mechanisms in both cell and animal models of Alzheimer’s disease. In HT22 cells co-cultured with lipopolysaccharide-induced RAW264.7/BV2 cells, extracellular vesicles overexpressing miR-146a significantly reduced the number of apoptotic cells and inhibited proinflammatory cytokine expression, nuclear factor (NF)-κB activation, and caspase-3/apoptosis regulator BAX signaling. These effects of extracellular vesicles overexpressing miR-146a were replicated in 5×FAD mice. In addition, extracellular vesicles overexpressing miR-146a inhibited the activation of microglia and astrocytes, reduced amyloid-β and phosphorylated tau expression, lowered the number of apoptotic cells in the hippocampus, and improved the cognitive function of these Alzheimer’s disease model mice. Mechanistically, miR-146a negatively regulated the expression of nuclear receptor subfamily 4 group A member 3 and suppressed the expression of proinflammatory cytokines and nuclear factor-κB signaling. Furthermore, NR4A3 overexpression promoted nuclear factor-κB and proinflammatory cytokine expression as well as nuclear factor-κB signaling. The upregulation of NR4A3 and the inflammatory response was reversed by miR-146a overexpression. Finally, NR4A3 was identified as a transcriptional activator of nuclear factor-κB using chromatin immunoprecipitation polymerase chain reaction. Collectively, these findings indicate that extracellular vesicles overexpressing miR-146a may alleviate the progression of Alzheimer’s disease by exerting anti-inflammatory effects via the NR4A3–nuclear factor-κB axis. They are thus a potential therapeutic candidate for the clinical treatment of neurodegenerative diseases.
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BibTeX
@article{zhang2026engineered,
title = {{Engineered mesenchymal stem cell-derived extracellular vesicles overexpressing miR-146a alleviate neuroinflammation in Alzheimer's disease.}},
author = {Jia Zhang and Siqi He and Qiguo Xiao and Weijie Jiang and Bo Wang and Jing Lu and Hong‐Feng Gu and Yajin Liao and Zhi Wang and Ying Xu and Dan Wang and Xiao‐Qing Tang and Ling Qi},
journal = {PubMed Central},
year = {2026},
month = oct,
doi = {10.4103/nrr.nrr-d-25-00404},
url = {https://pmc.ncbi.nlm.nih.gov/articles/PMC13568608/},
note = {CC BY},
}
RIS
TY - JOUR
TI - Engineered mesenchymal stem cell-derived extracellular vesicles overexpressing miR-146a alleviate neuroinflammation in Alzheimer's disease.
AU - Jia Zhang
AU - Siqi He
AU - Qiguo Xiao
AU - Weijie Jiang
AU - Bo Wang
AU - Jing Lu
AU - Hong‐Feng Gu
AU - Yajin Liao
AU - Zhi Wang
AU - Ying Xu
AU - Dan Wang
AU - Xiao‐Qing Tang
AU - Ling Qi
PY - 2026
DA - 2026/10/01
JO - PubMed Central
DO - 10.4103/nrr.nrr-d-25-00404
UR - https://pmc.ncbi.nlm.nih.gov/articles/PMC13568608/
AB - Alzheimer’s disease is an inflammatory neurodegenerative disease for which no effective clinical treatment currently exists. We have previously reported that mesenchymal stem cell–derived extracellular vesicles delay retinal degeneration by exerting anti-inflammatory effects though the miR-146a–nuclear receptor subfamily 4 group A member 3 axis; however, it remains unclear how NR4A3 drives inflammation. Herein, we engineered mesenchymal stem cell–derived extracellular vesicles overexpressing miR-146a to explore their possible neuroprotective effects and the underlying mechanisms in both cell and animal models of Alzheimer’s disease. In HT22 cells co-cultured with lipopolysaccharide-induced RAW264.7/BV2 cells, extracellular vesicles overexpressing miR-146a significantly reduced the number of apoptotic cells and inhibited proinflammatory cytokine expression, nuclear factor (NF)-κB activation, and caspase-3/apoptosis regulator BAX signaling. These effects of extracellular vesicles overexpressing miR-146a were replicated in 5×FAD mice. In addition, extracellular vesicles overexpressing miR-146a inhibited the activation of microglia and astrocytes, reduced amyloid-β and phosphorylated tau expression, lowered the number of apoptotic cells in the hippocampus, and improved the cognitive function of these Alzheimer’s disease model mice. Mechanistically, miR-146a negatively regulated the expression of nuclear receptor subfamily 4 group A member 3 and suppressed the expression of proinflammatory cytokines and nuclear factor-κB signaling. Furthermore, NR4A3 overexpression promoted nuclear factor-κB and proinflammatory cytokine expression as well as nuclear factor-κB signaling. The upregulation of NR4A3 and the inflammatory response was reversed by miR-146a overexpression. Finally, NR4A3 was identified as a transcriptional activator of nuclear factor-κB using chromatin immunoprecipitation polymerase chain reaction. Collectively, these findings indicate that extracellular vesicles overexpressing miR-146a may alleviate the progression of Alzheimer’s disease by exerting anti-inflammatory effects via the NR4A3–nuclear factor-κB axis. They are thus a potential therapeutic candidate for the clinical treatment of neurodegenerative diseases.
ER -