TY - JOUR
T1 - Small Extracellular Vesicles in Rat Serum Contain Astrocyte-Derived Protein Biomarkers of Repetitive Stress
AU - Gómez-Molina, Cristóbal
AU - Sandoval, Mauricio
AU - Henzi, Roberto
AU - Ramírez, Juan Pablo
AU - Varas-Godoy, Manuel
AU - Luarte, Alejandro
AU - Lafourcade, Carlos Andres
AU - Lopez-Verrilli, Alejandra
AU - Smalla, Karl Heinz
AU - Kaehne, Thilo
AU - Wyneken, Ursula
N1 - 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.
PY - 2018/12/8
Y1 - 2018/12/8
N2 - 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.
AB - 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.
KW - biomarkers
KW - exosomes
KW - stress subtypes
KW - biomarkers
KW - exosomes
KW - stress subtypes
UR - http://www.scopus.com/inward/record.url?scp=85062588251&partnerID=8YFLogxK
U2 - 10.1093/ijnp/pyy098
DO - 10.1093/ijnp/pyy098
M3 - Article
C2 - 30535257
AN - SCOPUS:85062588251
SN - 1461-1457
VL - 22
SP - 232
EP - 246
JO - International Journal of Neuropsychopharmacology
JF - International Journal of Neuropsychopharmacology
IS - 3
ER -