Small Extracellular Vesicles in Rat Serum Contain Astrocyte-Derived Protein Biomarkers of Repetitive Stress

Cristóbal Gómez-Molina, Mauricio Sandoval, Roberto Henzi, Juan Pablo Ramírez, Manuel Varas-Godoy, Alejandro Luarte, Carlos Andres Lafourcade, Alejandra Lopez-Verrilli, Karl Heinz Smalla, Thilo Kaehne, Ursula Wyneken*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

52 Scopus citations


Background: Stress precipitates mood disorders, characterized by a range of symptoms present in different combinations, suggesting the existence of disease subtypes. Using an animal model, we previously described that repetitive stress via restraint or immobilization induced depressive-like behaviors in rats that were differentially reverted by a serotonin- or noradrenaline-based antidepressant drug, indicating that different neurobiological mechanisms may be involved. The forebrain astrocyte protein aldolase C, contained in small extracellular vesicles, was identified as a potential biomarker in the cerebrospinal fluid; however, its specific origin remains unknown. Here, we propose to investigate whether serum small extracellular vesicles contain a stress-specific protein cargo and whether serum aldolase C has a brain origin. Methods: We isolated and characterized serum small extracellular vesicles from rats exposed to restraint, immobilization, or no stress, and their proteomes were identified by mass spectrometry. Data available via ProteomeXchange with identifier PXD009085 were validated, in part, by western blot. In utero electroporation was performed to study the direct transfer of recombinant aldolase C-GFP from brain cells to blood small extracellular vesicles. Results: A differential proteome was identified among the experimental groups, including aldolase C, astrocytic glial fibrillary acidic protein, synaptophysin, and reelin. Additionally, we observed that, when expressed in the brain, aldolase C tagged with green fluorescent protein could be recovered in serum small extracellular vesicles. Conclusion: The protein cargo of serum small extracellular vesicles constitutes a valuable source of biomarkers of stressinduced diseases, including those characterized by depressive-like behaviors. Brain-to-periphery signaling mediated by a differential molecular cargo of small extracellular vesicles is a novel and challenging mechanism by which the brain might communicate health and disease states to the rest of the body.

Original languageEnglish
Pages (from-to)232-246
Number of pages15
JournalInternational Journal of Neuropsychopharmacology
Issue number3
StatePublished - 8 Dec 2018

Bibliographical note

Funding Information:
This work was funded by the FONDECYT 1140108 project of the Chilean government and by the Santander Prize 2016.

Publisher Copyright:
© The Author(s) 2018.


  • biomarkers
  • exosomes
  • stress subtypes


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