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Harnessing the Power of MicroRNA Cargoes in Small Extracellular Vesicles Released from Fresh-Frozen Human Brain Sections
Published on: November 8, 2024
hUC-MSC-derived exosomes ameliorate Alzheimer's disease pathology through lncRNA-9969-mediated multi-target
Yan Zhang1, Fuqiang Zhang2, Hanlan Yin1
1Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, Edmond H. Fischer Transduction Signaling Laboratory, School of Life Science, Jilin University, Changchun, 130012, China.
Background:
Alzheimer's disease is characterized by intertwined pathologies including neuroinflammation, driven by microglial dysfunction, and metabolic disturbances such as lipid dyshomeostasis. Mesenchymal stem cell-derived exosomes (MSC-Exos) hold therapeutic promise, Still, it is unknown whether they can simultaneously address these co-occurring impairments via specific molecular cargos, such as long non-coding RNAs (lncRNAs).
Methods:
Transcriptome sequencing of exosomes derived from human umbilical cord mesenchymal stem cells (hUC-MSCs) revealed high expression of the long noncoding RNA ENST00000629969 (hereinafter referred to as lncRNA-9969). We isolated exosomes from hUC-MSCs (WT-Exo) and established human umbilical cord blood mesenchymal stem cells stably knocked down for lncRNA-9969 via siRNA, from which corresponding exosomes (KD-Exo) were isolated. Cross-species analysis identified the mouse homolog of lncRNA-9969 as ENSMUST00000200021 (hereinafter referred to as lncRNA-0021). Cellular experiments employed an Aβ₂₅₋₃₅-induced SH-SY5Y cell model to evaluate the protective effects of exosomes. In animal experiments, 6-month-old APP/PS1 mice received biweekly tail vein injections of WT-Exo or KD-Exo for 4 weeks. Phenotypic and mechanistic analyses were subsequently conducted using the Morris water maze, Western blot, immunofluorescence, qPCR, and transmission electron microscopy.
Results:
In Aβ-injured SH-SY5Y cells, WT-Exo significantly attenuated cellular damage and promoted Aβ clearance, whereas the protective effect of KD-Exo was markedly reduced. In APP/PS1 mice, WT-Exo treatment significantly improved spatial memory deficits and upregulated hippocampal expression of synaptic proteins synaptophysin (Syn) and brain-derived neurotrophic factor (BDNF). Molecular mechanism studies demonstrated that lncRNA-0021 directly binds mmu-miR-6361. Through this ceRNA mechanism, exosome-delivered lncRNA activated the mTOR/p70S6K autophagy pathway, regulated lipid metabolism-related genes, promoted microglial polarization toward the protective M2 phenotype, and suppressed pyroptosis. These beneficial changes were not observed in the KD-Exo-treated group.
Conclusions:
hUC-MSC-derived exosomes exert neuroprotective effects by delivering functional lncRNA-9969. Its highly conserved homolog in mice, lncRNA-0021, achieves coordinated multi-target regulation of neuroinflammation, pyroptosis, and metabolic disturbances by sequestering miR-6361 and activating downstream signaling pathways. This study elucidates the central role of exosomal lncRNAs in AD pathology and provides new insights for developing RNA-based multi-target therapeutic strategies.
Insights
Mesenchymal stem cell-derived exosomes carrying lncRNA-9969 show neuroprotective effects in Alzheimer's disease models. This exosomal long non-coding RNA targets miR-6361, regulating neuroinflammation and metabolism for potential RNA-based therapies.
Area of Science:
- Neuroscience
- Molecular Biology
- Biomedical Engineering
Background:
- Alzheimer's disease (AD) involves neuroinflammation and metabolic issues, with microglial dysfunction and lipid dyshomeostasis as key features.
- Mesenchymal stem cell-derived exosomes (MSC-Exos) show therapeutic potential, but their ability to address multiple AD pathologies via specific cargos like long non-coding RNAs (lncRNAs) is unclear.
Purpose of the Study:
- To investigate if lncRNA-9969 delivered by MSC-Exos can simultaneously ameliorate neuroinflammation and metabolic disturbances in Alzheimer's disease.
- To elucidate the molecular mechanisms underlying the therapeutic effects of exosomal lncRNA-9969 in AD models.
Main Methods:
- Transcriptome sequencing identified lncRNA-9969 in human umbilical cord MSC-derived exosomes (hUC-MSCs).
- Exosomes with normal (WT-Exo) or knocked-down (KD-Exo) lncRNA-9969 levels were generated and tested in Aβ-injured SH-SY5Y cells and APP/PS1 mice.
- Phenotypic and mechanistic analyses included behavioral tests, Western blot, immunofluorescence, qPCR, and electron microscopy.
Main Results:
- WT-Exo, but not KD-Exo, protected SH-SY5Y cells from Aβ-induced damage and enhanced Aβ clearance.
- In APP/PS1 mice, WT-Exo improved spatial memory and upregulated synaptic proteins.
- Exosomal lncRNA-0021 (mouse homolog) bound miR-6361, activating mTOR/p70S6K autophagy, regulating lipid metabolism, promoting M2 microglial polarization, and suppressing pyroptosis.
Conclusions:
- hUC-MSC-derived exosomes deliver functional lncRNA-9969, exerting neuroprotection in AD.
- Exosomal lncRNA-0021 orchestrates multi-target regulation of neuroinflammation, pyroptosis, and lipid metabolism via the miR-6361/mTOR pathway.
- This highlights the therapeutic potential of exosomal lncRNAs for Alzheimer's disease.
