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

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

doi:10.1093/ijnp/pyy098

Cited by 65 publications

(80 citation statements)

References 59 publications

(71 reference statements)

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“…Similar signaling, but in the opposite way, has been shown to occur in humans, where fetal-derived exosome-like vesicles reach to the maternal blood stream [82]. Interestingly, growing evidence shows that exosome-like vesicles from astrocytic origin may reach the blood stream [19], [83] and thus may have the capacity to signal to peripheral organs or body systems.…”

Section: Astrocyte-derived Sevs In Neurological Conditionsmentioning

confidence: 75%

“…sEVs were analyzed with the NanoSight LM-10 device (Malvern Instruments) equipped with a green laser, as described in [19].…”

Section: Nanoparticle Tracking Analysis (Nta)mentioning

confidence: 99%

“…Aldolase C is an astrocytic and cytoplasmic glycolytic enzyme released in sEVs/exosome-like fractions [17]- [19]. We characterized the sEV fractions from cultured astrocytes by ultracentrifugation and Western blot analysis.…”

Section: Astrocytes Transfer Aldolase C-gfp-containing Sevs To Neuronsmentioning

confidence: 99%

“…On a different approach, Aldo C phosphorylation pattern is modified on the cerebrospinal fluid (CSF) of patients with major depressive disorder [74]. Furthermore, our group has shown that extracellular levels of Aldo C were highly up-regulated in a microsomal brain sub-fraction and in rat CSF after treatment with the antidepressant drug fluoxetine and in CSF and serum sEVs of rats exposed to stress by movement restriction [17], [18], [19]. Thus, we speculate that increased presence of Aldo C in astrocytes, as well as sEVs, may potentially reproduce the herein-described effects over dendritic structure of hippocampal neurons in pathological conditions.…”

Section: Astrocyte-derived Sevs In Neurological Conditionsmentioning

confidence: 99%

“…We have shown that the astrocyte's specific glycolytic enzyme Aldolase C (Aldo C) is present in sEVs and that its content is regulated in vivo and in vitro: Astrocyte-derived sEVs contain Aldo C and its levels increase in rat cerebrospinal fluid and in serum sEVs with stress induced by movement restriction [17]- [19]. In addition, we have recently shown that Aldo C expressed in brain astrocytes can be collected in sEVs isolated from rat blood serum, supporting the capacity of astrocyte-derived sEVs to cross biological barriers and to serve as regulators of intercellular signaling [19]. However, it is not known whether neurons, which are in close proximity to neurons, can incorporate astrocytederived sEVs containing Aldo C nor whether they can impact neuronal function.…”

Section: Introductionmentioning

confidence: 99%

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Astrocyte-Derived Small Extracellular Vesicles Regulate Dendritic Complexity through miR-26a-5p Activity

Luarte¹,

Henzi²,

Fernández³

et al. 2020

Preprint

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In the last decades, it has been established that astrocytes play key roles in the regulation of neuronal morphology. However, the contribution of astrocyte-derived small extracellular vesicles (sEVs) to morphological differentiation of neurons has only recently been addressed. Here, we showed that cultured astrocytes expressing a GFP tagged version of the stress-regulated astrocytic enzyme Aldolase C (Aldo C-GFP) release small extracellular vesicles (sEVs) which are transferred into cultured hippocampal neurons. Surprisingly, Aldo C-GFP-containing sEVs (Aldo C-GFP sEVs) displayed an exacerbated capacity to reduce the dendritic complexity in developing hippocampal neurons compared to sEVs derived from control (i.e. GFP-expressing) astrocytes. Using bioinformatics and biochemical tools, we found that the total content of overexpressed Aldo C-GFP correlates with an increased content of endogenous miRNA-26a-5p in both total astrocyte homogenates and sEVs. Notably, neurons magnetofected with a nucleotide sequence that mimics endogenous miRNA-26a-5p (mimic 26a-5p) not only decreased the levels of neuronal proteins associated to morphogenesis regulation and also reproduced morphological changes induced by Aldo-C-GFP sEVs. Furthermore, neurons magnetofected with a sequence targeting miRNA-26a-5p (antago 26a-5p) were largely resistant to Aldo C-GFP sEVs. Our results support a novel and complex level of astrocyte-to-neuron communication mediated by astrocyte-derived sEVs and the activity of their miRNA content.Here, we showed that cultured astrocytes that express GFP-tagged Aldo C (Aldo C-GFP) transfer the derived sEVs, carrying the recombinant protein, in order to develop hippocampal neurons, impacting on their dendritic complexity. Using bioinformatics combined with biochemical and molecular approaches, we postulated and then confirmed that the content of miRNA-26a-5 is regulated in Aldo C-GFP-electroporated astrocytes and their sEVs. Finally, we showed that the miRNA-26a-5p-carried by Aldo C-GFP-containing sEVs (Aldo C-GFP sEVs) actively regulate the expression of some relevant neuronal proteins for morphogenesis and dendritic complexity. Our results show that sEVs from astrocytes can regulate dendritic complexity depending on the activity of miRNA-26a-5p.. Preprints (www.preprints.org) | NOT PEER-REVIEWED |

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Section: Astrocyte-derived Sevs In Neurological Conditionsmentioning

confidence: 75%

“…sEVs were analyzed with the NanoSight LM-10 device (Malvern Instruments) equipped with a green laser, as described in [19].…”

Section: Nanoparticle Tracking Analysis (Nta)mentioning

confidence: 99%

Section: Astrocytes Transfer Aldolase C-gfp-containing Sevs To Neuronsmentioning

confidence: 99%

Section: Astrocyte-derived Sevs In Neurological Conditionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Astrocyte-Derived Small Extracellular Vesicles Regulate Dendritic Complexity through miR-26a-5p Activity

Luarte¹,

Henzi²,

Fernández³

et al. 2020

Preprint

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Implication of cerebral astrocytes in major depression: A review of fine neuroanatomical evidence in humans

O’Leary

Mechawar

2021

Glia

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Postmortem investigations have implicated astrocytes in many neurological and psychiatric conditions. Multiple brain regions from individuals with major depressive disorder (MDD) have lower expression levels of astrocyte markers and lower densities of astrocytes labeled for these markers, suggesting a loss of astrocytes in this mental illness. This paper reviews the general properties of human astrocytes, the methods to study them, and the postmortem evidence for astrocyte pathology in MDD. When comparing astrocyte density and morphometry studies, astrocytes are more abundant and smaller in human subcortical than cortical brain regions, and immunohistochemical labeling for the astrocyte markers glial fibrillary acidic protein (GFAP) and vimentin (VIM) reveals fewer than 15% of all astrocytes that are present in cortical and subcortical regions, as revealed using other staining techniques. By combining astrocyte densities and morphometry, a model was made to illustrate that domain organization is mostly limited to GFAP‐IR astrocytes. Using these markers and others, alterations of astrocyte densities appear more widespread than those for astrocyte morphologies throughout the brain of individuals having died with MDD. This review suggests how reduced astrocyte densities may relate to the association of depressive episodes in MDD with elevated S100 beta (S100B) cerebrospinal fluid serum levels. Finally, a potassium imbalance theory is proposed that integrates the reduced astrocyte densities generated from postmortem studies with a hypothesis for the antidepressant effects of ketamine generated from rodent studies.

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Exosomes as drug delivery vehicles and biomarkers for neurological and auditory systems

Mittal

Bencie

Langlie

et al. 2021

Journal Cellular Physiology

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Exosomes are small extracellular membrane particles that play a crucial role in intracellular signaling. Research shows that exosomes have the potential to be used as biomarkers or drug delivery systems in specific organs, such as the neurological system and the inner ear. Exosomes in neurological and auditory systems release different molecules when under stress versus in healthy states, highlighting their potential use as biomarkers in the identification of diseased states. Studies have suggested that exosomes can be harnessed for drug delivery to hard-to-reach organs, such as cochlear sensory hair cells and the brain due to their ability to cross the blood-labyrinth and blood-brain barriers. In this article, we describe the biogenesis, classification, and characterization methods of exosomes. We then discuss recent studies that indicate their potential usage as biomarkers and drug delivery systems to help treat inner ear and neurological disorders.

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

Cited by 65 publications

References 59 publications

Astrocyte-Derived Small Extracellular Vesicles Regulate Dendritic Complexity through miR-26a-5p Activity

Astrocyte-Derived Small Extracellular Vesicles Regulate Dendritic Complexity through miR-26a-5p Activity

Implication of cerebral astrocytes in major depression: A review of fine neuroanatomical evidence in humans

Exosomes as drug delivery vehicles and biomarkers for neurological and auditory systems

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