Peripheral blood exosomes pass blood-brain-barrier and induce glial cell activation

Morales-Prieto, Diana M.; Stojiljkovic, Milan; Diezel, Celia; Streicher, Priska-Elisabeth; Röstel, Franziska; Lindner, Julia; Weis, Sebastian; Schmeer, Christian; Marz, Manja

doi:10.1101/471409

Cited by 11 publications

(9 citation statements)

References 21 publications

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“…However, the relative abundance of astrocyte α-syn arising from different sources (i.e., neuronal, peripheral, or endogenously expressed) remains to be determined. Regardless of what proportion of astrocytic α-syn is derived from peripheral sources, in agreement with our observation, a recent study demonstrated evidence that peripheral injection of blood EVs derived from aged mice activate astrocytes [55], further indicating that astrocytes play a critical role in response to peripheralderived EVs. In addition, stroke-induced enhanced BBB permeability promotes EVs and pro-inflammatory factors passing through the BBB, resulting in abnormal activation of astrocytes [59,103].…”

Section: Implications Of Peripheral α-Syn Contribution To Parkinson'ssupporting

confidence: 92%

Erythrocytic α-synuclein contained in microvesicles regulates astrocytic glutamate homeostasis: a new perspective on Parkinson’s disease pathogenesis

Sheng

Stewart

Yang

et al. 2020

acta neuropathol commun

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Parkinson's disease is a neurodegenerative disorder characterized by the transmission and accumulation of toxic species of α-synuclein (α-syn). Extracellular vesicles (EVs) are believed to play a vital role in the spread of toxic α-syn species. Recently, peripheral α-syn pathology has been investigated, but little attention has been devoted to erythrocytes, which contain abundant α-syn. In this study, we first demonstrated that erythrocyte-derived EVs isolated from Parkinson's disease patients carried elevated levels of oligomeric α-syn, compared to those from healthy controls. Moreover, human erythrocyte-derived EVs, when injected into peripheral blood in a mouse model of Parkinson's disease, were found to readily cross the blood-brain barrier (BBB). These EVs accumulated in astrocyte endfeet, a component of the BBB, where they impaired glutamate uptake, likely via interaction between excitatory amino acid transporter 2 (EAAT2) and oligomeric α-syn. These data suggest that erythrocyte-derived EVs and the oligomeric α-syn carried in them may play critical roles in the progression or even initiation of Parkinson's disease. Additionally, the mechanisms involved are attributable at least in part to dysfunction of astrocytes induced by these EVs. These observations provide new insight into the understanding of the mechanisms involved in Parkinson's disease.

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Section: Implications Of Peripheral α-Syn Contribution To Parkinson'ssupporting

confidence: 92%

Erythrocytic α-synuclein contained in microvesicles regulates astrocytic glutamate homeostasis: a new perspective on Parkinson’s disease pathogenesis

Sheng

Stewart

Yang

et al. 2020

acta neuropathol commun

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“…The BBB restricts large molecule drug delivery, as well as 98% of small molecule drug delivery, which poses an issue for many therapeutic platforms [31]. However, exosomes have been shown in multiple studies to cross the BBB and deliver a therapeutic payload, making them an advantageous platform in regenerative medicine as well as treatment of neurological disorders [32,33]. All of these factors make exosomes an ideal vehicle for drug delivery for many applications, including drug delivery in the treatment of various diseases including heart disease.…”

Section: Exosomes For Drug Delivery Purposesmentioning

confidence: 99%

Exosome and Biomimetic Nanoparticle Therapies for Cardiac Regenerative Medicine

Stine

Popowski

et al. 2020

CSCR

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: Exosome and biomimetic nanoparticles have great potential to develop into a wide-scale therapeutic platform within the regenerative medicine industry. Exosomes, a subgroup of EVs whose diameter ranges from 30-100 nm, have recently gained traction as an innovative approach for the treatment of various diseases, including heart disease. Their beneficial factors and regenerative properties can be contrasted between various cell types. Various biomimetic nanoparticles have also emerged as a unique platform in regenerative medicine. Biomimetic nanoparticles are a drug delivery platform that have the ability to contain both biological and fabricated components to improve therapeutic efficiency and targeting. The novelty of these platforms holds promise for future clinical translation upon further investigation. In order for both exosome therapeutics and biomimetic nanoparticles to translate to large-scale clinical treatment, numerous factors must first be considered and improved. Standardization of different protocols, from exosome isolation to storage conditions, must be optimized to ensure batches are pure. Standardization is also important to ensure there is no variability in this process across studies, thus making it easier to interpret data across different disease models and treatments. Expansion of clinical trials incorporating both biomimetic nanoparticles and exosomes will require a standardization of fabrication and isolation techniques, as well as stricter regulations to ensure reproducibility across various studies and disease models. This review will summarize current research on exosome therapeutics and the application of biomimetic nanoparticles in cardiac regenerative medicine, as well as applications for exosome expansion and delivery on a larger and more clinical scale.

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“…Our present study verified the exosome role in transporting NEAT1 into the cerebral cortex through BBB, consistent with that reported by other researchers fz. Morales-Prieto et al [33] indicated that exosomes could pass through BBB and act on glial cell activation. Reynolds et al [34] revealed that human microglial cells exosomes cross the BBB and are efficient delivery vehicles to the CNS.…”

Section: Discussionmentioning

confidence: 99%

Exosome-Derived lncRNA NEAT1 Exacerbates Sepsis-Associated Encephalopathy by Promoting Ferroptosis Through Regulating miR-9-5p/TFRC and GOT1 Axis

et al. 2022

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Sepsis can cause sepsis-associated encephalopathy (SAE), but whether SAE was induced or exacerbated by ferroptosis remains unknown. In this study, the rat sepsis model was constructed using the cecal ligation and puncture method. The blood–brain barrier (BBB) permeability was measured by Evans blue dye (EBD) in vivo. The levels of ROS, Fe ion, MDA, GSH, and GPX4 were assessed by enzyme-linked immunosorbent assay (ELISA). The exosomes isolated from serum were cultured with bEnd.3 cells for the in vitro analysis. Moreover, bEnd.3 cells cultured with 100 μM FeCl3 (iron-rich) were to simulate ferroptosis stress. The cell viability was evaluated by Cell Counting Kit-8 (CCK-8) assay. A dual-luciferase reporter gene assay was performed to confirm the relationship between miR-9-5p with NEAT1, TFRC, and GOT1. In vivo, it is found that BBB permeability was damaged in model rats. Level of ROS, Fe ion, and MDA was increased, and level of GSH and GPX4 was decreased, which means ferroptosis was induced by sepsis. Exosome-packaged NEAT1 in serum was significantly upregulated in model rats. In vitro, it is found that NEAT1 functions as a ceRNA for miR-9-5p to facilitate TFRC and GOT1 expression. Overexpression of NEAT1 enhanced ferroptosis stress in bEnd.3 cells. Increased miR-9-5p alleviated sepsis-induced ferroptosis by suppressing the expression of TFRC and GOT1 both in vivo and in vitro. In conclusion, these findings suggest that sepsis induced high expression of serous exosome-derived NEAT1, and it might exacerbate SAE by promoting ferroptosis through regulating miR-9-5p/TFRC and GOT1 axis.

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Peripheral blood exosomes pass blood-brain-barrier and induce glial cell activation

Cited by 11 publications

References 21 publications

Erythrocytic α-synuclein contained in microvesicles regulates astrocytic glutamate homeostasis: a new perspective on Parkinson’s disease pathogenesis

Erythrocytic α-synuclein contained in microvesicles regulates astrocytic glutamate homeostasis: a new perspective on Parkinson’s disease pathogenesis

Exosome and Biomimetic Nanoparticle Therapies for Cardiac Regenerative Medicine

Exosome-Derived lncRNA NEAT1 Exacerbates Sepsis-Associated Encephalopathy by Promoting Ferroptosis Through Regulating miR-9-5p/TFRC and GOT1 Axis

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