Plain-language summary
Major depressive disorder does not always respond to existing medication, so researchers are looking at cell-derived carriers that can reach the brain without surgery. In this study, exosomes released by adipose-derived mesenchymal stem cells were given to mice as a nasal spray. After chronic restraint stress, the animals that received them showed less depressive-like and anxiety-like behaviour and performed better on cognitive tasks. At tissue level the treatment reduced neuronal death and calmed over-activated microglia, the immune cells that sustain low-grade brain inflammation. On the molecular side, the exosomes switched on AMPK signalling while damping mTOR activity, which restored autophagy — the cell's own waste-recycling programme — and lowered activation of the NLRP3 inflammasome. Levels of circulating inflammatory cytokines fell in parallel. Similar effects appeared in cultured hippocampal neurons stressed with corticosterone, where apoptosis was reduced and autophagy increased in an AMPK-dependent manner. Because the nasal route sidesteps the blood-brain barrier, the authors present this as a candidate strategy worth exploring for depression, while noting the work remains preclinical.
Key findings
- Adipose-derived mesenchymal stem cell exosomes were delivered intranasally to mice exposed to chronic restraint stress.
- Treated animals showed fewer depressive-like and anxiety-like behaviours and better cognitive performance.
- The exosomes activated AMPK signalling, restored autophagy and limited NLRP3 inflammasome activation, which reduced neuroinflammation and neuronal apoptosis.
- The findings come from mice and cultured cells, so the approach remains at the preclinical stage.
Original abstract
Background: Major depressive disorder (MDD) is a severe, and often treatment-resistant, psychiatric disorder. Mesenchymal stem cell-derived exosomes have been shown to be neuroprotective. Here we employed adipose-derived mesenchymal stem cell exosomes (ADSC-Exos) as a novel therapeutic approach for depressive-like behavior in mice and explored the underlying mechanisms. Methods: ADSC-Exos were administered intranasally to mice subjected to chronic restraint stress to assess behavioral changes and neuroprotection in terms of apoptosis, AMPK-mTOR signaling, and NLRP3 pathway activation by western blotting, microglial activation by immunofluorescence, and changes in serum inflammatory factors by ELISA. The effects of ADSC-Exos were also studied in vitro in HT22 cells. Results: ADSC-Exos significantly improved depressive-like behavior, anxiety-like behavior, and cognitive function in mice. ADSC-Exos had significant neuroprotective effects, including reducing neuronal apoptosis and promoting autophagy by activating AMPK-mTOR signaling, ultimately reducing neuroinflammation. In vitro, ADSC-Exos inhibited corticosterone-induced apoptosis, activated autophagy in an AMPK pathway-dependent manner, and inhibited NLRP3 inflammasome activation. Conclusion: ADSC-Exos may be a potential treatment for MDD by alleviating depressive-like behaviors and protecting against tissue injury, possibly through activation of AMPK-mTOR signaling and inhibition of NLRP3 inflammasome-mediated neuroinflammation.
Frequently asked questions
What did this study find?
Major depressive disorder does not always respond to existing medication, so researchers are looking at cell-derived carriers that can reach the brain without surgery. In this study, exosomes released by adipose-derived mesenchymal stem cells were given to mice as a nasal spray. After chronic restraint stress, the animals that received them showed less depressive-like and anxiety-like behaviour and performed better on cognitive tasks. At tissue level the treatment reduced neuronal death and calmed over-activated microglia, the immune cells that sustain low-grade brain inflammation. On the molecular side, the exosomes switched on AMPK signalling while damping mTOR activity, which restored autophagy — the cell's own waste-recycling programme — and lowered activation of the NLRP3 inflammasome. Levels of circulating inflammatory cytokines fell in parallel. Similar effects appeared in cultured hippocampal neurons stressed with corticosterone, where apoptosis was reduced and autophagy increased in an AMPK-dependent manner. Because the nasal route sidesteps the blood-brain barrier, the authors present this as a candidate strategy worth exploring for depression, while noting the work remains preclinical.
Was this tested in humans or in the laboratory?
This is preclinical work — the findings come from laboratory models, not from human participants.
Where can I read the original paper?
The full text lives with the publisher: https://doi.org/10.1016/j.jad.2025.04.059
How to cite this paper
Sun Siqi, Rong Jingtong, Wang Chao, Li Ruiling, Zhang Honghan, Wang Wei et al.. Intranasal administration of exosomes derived from adipose mesenchymal stem cells ameliorates depressive-like behaviors and inhibits inflammation via AMPK/mTOR-mediated autophagy.. Journal of affective disorders. 2025, 2025-04-18. DOI: 10.1016/j.jad.2025.04.059
Source & verification
- Journal: Journal of affective disorders
- Published: 18 April 2025
- DOI: 10.1016/j.jad.2025.04.059
- PubMed ID: 40250814
- Indexed via: pubmed
- MeSH terms: Animals, Exosomes, Autophagy, TOR Serine-Threonine Kinases, Mice, Mesenchymal Stem Cells, AMP-Activated Protein Kinases, Administration, Intranasal, Male, Signal Transduction, NLR Family, Pyrin Domain-Containing 3 Protein, Apoptosis