International Journal of Molecular Sciences

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12 pages, 5609 KiB

Open AccessArticle

Ubiquinone Metabolism and Transcription HIF-1 Targets Pathway Are Toxicity Signature Pathways Present in Extracellular Vesicles of Paraquat-Exposed Human Brain Microvascular Endothelial Cells

by Tatjana Vujić, Domitille Schvartz, Anton Iliuk and Jean-Charles Sanchez

Int. J. Mol. Sci. 2021, 22(10), 5065; https://doi.org/10.3390/ijms22105065 - 11 May 2021

Cited by 5 | Viewed by 2380

Abstract

Over the last decade, the knowledge in extracellular vesicles (EVs) biogenesis and modulation has increasingly grown. As their content reflects the physiological state of their donor cells, these “intercellular messengers” progressively became a potential source of biomarker reflecting the host cell state. However, [...] Read more.

Over the last decade, the knowledge in extracellular vesicles (EVs) biogenesis and modulation has increasingly grown. As their content reflects the physiological state of their donor cells, these “intercellular messengers” progressively became a potential source of biomarker reflecting the host cell state. However, little is known about EVs released from the human brain microvascular endothelial cells (HBMECs). The current study aimed to isolate and characterize EVs from HBMECs and to analyze their EVs proteome modulation after paraquat (PQ) stimulation, a widely used herbicide known for its neurotoxic effect. Size distribution, concentration and presence of well-known EV markers were assessed. Identification and quantification of PQ-exposed EV proteins was conducted by data-independent acquisition mass spectrometry (DIA-MS). Signature pathways of PQ-treated EVs were analyzed by gene ontology terms and pathway enrichment. Results highlighted that EVs exposed to PQ have modulated pathways, namely the ubiquinone metabolism and the transcription HIF-1 targets. These pathways may be potential molecular signatures of the PQ-induced toxicity carried by EVs that are reflecting their cell of origin by transporting with them irreversible functional changes. Full article

(This article belongs to the Special Issue Role and Dynamics of Extracellular Vesicles in Central Nervous System Diseases)

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17 pages, 1980 KiB

Open AccessArticle

Proteomics Profiling of Neuron-Derived Small Extracellular Vesicles from Human Plasma: Enabling Single-Subject Analysis

by Federica Anastasi, Silvia Maria Masciandaro, Renata Del Carratore, Maria Teresa Dell’Anno, Giovanni Signore, Alessandra Falleni, Liam A. McDonnell and Paolo Bongioanni

Int. J. Mol. Sci. 2021, 22(6), 2951; https://doi.org/10.3390/ijms22062951 - 14 Mar 2021

Cited by 31 | Viewed by 5550

Abstract

Small extracellular vesicles have been intensively studied as a source of biomarkers in neurodegenerative disorders. The possibility to isolate neuron-derived small extracellular vesicles (NDsEV) from blood represents a potential window into brain pathological processes. To date, the absence of sensitive NDsEV isolation and [...] Read more.

Small extracellular vesicles have been intensively studied as a source of biomarkers in neurodegenerative disorders. The possibility to isolate neuron-derived small extracellular vesicles (NDsEV) from blood represents a potential window into brain pathological processes. To date, the absence of sensitive NDsEV isolation and full proteome characterization methods has meant their protein content has been underexplored, particularly for individual patients. Here, we report a rapid method based on an immunoplate covalently coated with mouse monoclonal anti-L1CAM antibody for the isolation and the proteome characterization of plasma-NDsEV from individual Parkinson’s disease (PD) patients. We isolated round-shaped vesicles with morphological characteristics consistent with exosomes. On average, 349 ± 38 protein groups were identified by liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis, 20 of which are annotated in the Human Protein Atlas as being highly expressed in the brain, and 213 were shared with a reference NDsEV dataset obtained from cultured human neurons. Moreover, this approach enabled the identification of 23 proteins belonging to the Parkinson disease KEGG pathway, as well as proteins previously reported as PD circulating biomarkers. Full article

(This article belongs to the Special Issue Role and Dynamics of Extracellular Vesicles in Central Nervous System Diseases)

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12 pages, 1356 KiB

Open AccessArticle

GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson’s Disease

by Silvia Cerri, Cristina Ghezzi, Gerardo Ongari, Stefania Croce, Micol Avenali, Roberta Zangaglia, Donato A. Di Monte, Enza Maria Valente and Fabio Blandini

Int. J. Mol. Sci. 2021, 22(4), 2215; https://doi.org/10.3390/ijms22042215 - 23 Feb 2021

Cited by 20 | Viewed by 3918

Abstract

Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), are the strongest known genetic risk factor for Parkinson’s disease (PD). The molecular mechanisms underlying the increased PD risk and the variable phenotypes observed in carriers of different GBA mutations are [...] Read more.

Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), are the strongest known genetic risk factor for Parkinson’s disease (PD). The molecular mechanisms underlying the increased PD risk and the variable phenotypes observed in carriers of different GBA mutations are not yet fully elucidated. Extracellular vesicles (EVs) have gained increasing importance in neurodegenerative diseases since they can vehiculate pathological molecules potentially promoting disease propagation. Accumulating evidence showed that perturbations of the endosomal–lysosomal pathway can affect EV release and composition. Here, we investigate the impact of GCase deficiency on EV release and their effect in recipient cells. EVs were purified by ultracentrifugation from the supernatant of fibroblast cell lines derived from PD patients with or without GBA mutations and quantified by nanoparticle tracking analysis. SH-SY5Y cells over-expressing alpha-synuclein (α-syn) were used to assess the ability of patient-derived small EVs to affect α-syn expression. We observed that defective GCase activity promotes the release of EVs, independently of mutation severity. Moreover, small EVs released from PD fibroblasts carrying severe mutations increased the intra-cellular levels of phosphorylated α-syn. In summary, our work shows that the dysregulation of small EV trafficking and alpha-synuclein mishandling may play a role in GBA-associated PD. Full article

(This article belongs to the Special Issue Role and Dynamics of Extracellular Vesicles in Central Nervous System Diseases)

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18 pages, 2935 KiB

Open AccessArticle

Molecular Characterization of Temozolomide-Treated and Non Temozolomide-Treated Glioblastoma Cells Released Extracellular Vesicles and Their Role in the Macrophage Response

by Elisa Panzarini, Stefano Tacconi, Elisabetta Carata, Stefania Mariano, Ada Maria Tata and Luciana Dini

Int. J. Mol. Sci. 2020, 21(21), 8353; https://doi.org/10.3390/ijms21218353 - 7 Nov 2020

Cited by 20 | Viewed by 3068

Abstract

Extracellular vesicles (EVs) are widely investigated in glioblastoma multiforme (GBM) for their involvement in regulating GBM pathobiology as well as for their use as potential biomarkers. EVs, through cell-to-cell communication, can deliver proteins, nucleic acids, and lipids that are able to reprogram tumor-associated [...] Read more.

Extracellular vesicles (EVs) are widely investigated in glioblastoma multiforme (GBM) for their involvement in regulating GBM pathobiology as well as for their use as potential biomarkers. EVs, through cell-to-cell communication, can deliver proteins, nucleic acids, and lipids that are able to reprogram tumor-associated macrophages (TAMs). This research is aimed to concentrate, characterize, and identify molecular markers of EVs subtypes released by temozolomide (TMZ)-treated and non TMZ-treated four diverse GBM cells. Morphology, size distribution, and quantity of small (sEVs) and large (lEVs) vesicles were analyzed by cryo-TEM. Quality and quantity of EVs surface markers were evaluated, having been obtained by Western blotting. GBM cells shed a large amount of EVs, showing a cell line dependent molecular profile A comparative analysis distinguished sEVs and lEVs released by temozolomide (TMZ)-treated and non TMZ-treated GBM cells on the basis of quantity, size and markers expression. Finally, the GBM-derived sEVs and lEVs, irrespective of TMZ treatment, when challenged with macrophages, modulated cell activation toward a tendentially M2b-like phenotype. Full article

(This article belongs to the Special Issue Role and Dynamics of Extracellular Vesicles in Central Nervous System Diseases)

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21 pages, 5262 KiB

Open AccessArticle

Transport of Extracellular Vesicles across the Blood-Brain Barrier: Brain Pharmacokinetics and Effects of Inflammation

by William A. Banks, Priyanka Sharma, Kristin M. Bullock, Kim M. Hansen, Nils Ludwig and Theresa L. Whiteside

Int. J. Mol. Sci. 2020, 21(12), 4407; https://doi.org/10.3390/ijms21124407 - 21 Jun 2020

Cited by 283 | Viewed by 9770

Abstract

Extracellular vesicles can cross the blood–brain barrier (BBB), but little is known about passage. Here, we used multiple-time regression analysis to examine the ability of 10 exosome populations derived from mouse, human, cancerous, and non-cancerous cell lines to cross the BBB. All crossed [...] Read more.

Extracellular vesicles can cross the blood–brain barrier (BBB), but little is known about passage. Here, we used multiple-time regression analysis to examine the ability of 10 exosome populations derived from mouse, human, cancerous, and non-cancerous cell lines to cross the BBB. All crossed the BBB, but rates varied over 10-fold. Lipopolysaccharide (LPS), an activator of the innate immune system, enhanced uptake independently of BBB disruption for six exosomes and decreased uptake for one. Wheatgerm agglutinin (WGA) modulated transport of five exosome populations, suggesting passage by adsorptive transcytosis. Mannose 6-phosphate inhibited uptake of J774A.1, demonstrating that its BBB transporter is the mannose 6-phosphate receptor. Uptake rates, patterns, and effects of LPS or WGA were not predicted by exosome source (mouse vs. human) or cancer status of the cell lines. The cell surface proteins CD46, AVβ6, AVβ3, and ICAM-1 were variably expressed but not predictive of transport rate nor responses to LPS or WGA. A brain-to-blood efflux mechanism variably affected CNS retention and explains how CNS-derived exosomes enter blood. In summary, all exosomes tested here readily crossed the BBB, but at varying rates and by a variety of vesicular-mediated mechanisms involving specific transporters, adsorptive transcytosis, and a brain-to-blood efflux system. Full article

(This article belongs to the Special Issue Role and Dynamics of Extracellular Vesicles in Central Nervous System Diseases)

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Review

Jump to: Research

17 pages, 1371 KiB

Open AccessReview

Living Proof of Activity of Extracellular Vesicles in the Central Nervous System

by Shadi Mahjoum, David Rufino-Ramos, Luís Pereira de Almeida, Marike L. D. Broekman, Xandra O. Breakefield and Thomas S. van Solinge

Int. J. Mol. Sci. 2021, 22(14), 7294; https://doi.org/10.3390/ijms22147294 - 7 Jul 2021

Cited by 9 | Viewed by 3442

Abstract

The central nervous system (CNS) consists of a heterogeneous population of cells with highly specialized functions. For optimal functioning of the CNS, in disease and in health, intricate communication between these cells is vital. One important mechanism of cellular communication is the release [...] Read more.

The central nervous system (CNS) consists of a heterogeneous population of cells with highly specialized functions. For optimal functioning of the CNS, in disease and in health, intricate communication between these cells is vital. One important mechanism of cellular communication is the release and uptake of extracellular vesicles (EVs). EVs are membrane enclosed particles actively released by cells, containing a wide array of proteins, lipids, RNA, and DNA. These EVs can be taken up by neighboring or distant cells, and influence a wide range of processes. Due to the complexity and relative inaccessibility of the CNS, our current understanding of the role of EVs is mainly derived in vitro work. However, recently new methods and techniques have opened the ability to study the role of EVs in the CNS in vivo. In this review, we discuss the current developments in our understanding of the role of EVs in the CNS in vivo. Full article

(This article belongs to the Special Issue Role and Dynamics of Extracellular Vesicles in Central Nervous System Diseases)

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19 pages, 5200 KiB

Open AccessReview

Exosomes: Small EVs with Large Immunomodulatory Effect in Glioblastoma

by Laura Benecke, Mali Coray, Sandra Umbricht, Dapi Chiang, Fabrício Figueiró and Laurent Muller

Int. J. Mol. Sci. 2021, 22(7), 3600; https://doi.org/10.3390/ijms22073600 - 30 Mar 2021

Cited by 18 | Viewed by 3600

Abstract

Glioblastomas are among the most aggressive tumors, and with low survival rates. They are characterized by the ability to create a highly immunosuppressive tumor microenvironment. Exosomes, small extracellular vesicles (EVs), mediate intercellular communication in the tumor microenvironment by transporting various biomolecules (RNA, DNA, [...] Read more.

Glioblastomas are among the most aggressive tumors, and with low survival rates. They are characterized by the ability to create a highly immunosuppressive tumor microenvironment. Exosomes, small extracellular vesicles (EVs), mediate intercellular communication in the tumor microenvironment by transporting various biomolecules (RNA, DNA, proteins, and lipids), therefore playing a prominent role in tumor proliferation, differentiation, metastasis, and resistance to chemotherapy or radiation. Exosomes are found in all body fluids and can cross the blood–brain barrier due to their nanoscale size. Recent studies have highlighted the multiple influences of tumor-derived exosomes on immune cells. Owing to their structural and functional properties, exosomes can be an important instrument for gaining a better molecular understanding of tumors. Furthermore, they qualify not only as diagnostic and prognostic markers, but also as tools in therapies specifically targeting aggressive tumor cells, like glioblastomas. Full article

(This article belongs to the Special Issue Role and Dynamics of Extracellular Vesicles in Central Nervous System Diseases)

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32 pages, 1731 KiB

Open AccessReview

Secreted Extracellular Vesicle Molecular Cargo as a Novel Liquid Biopsy Diagnostics of Central Nervous System Diseases

by Sara Monteiro-Reis, Carina Carvalho-Maia, Genevieve Bart, Seppo J. Vainio, Juliana Pedro, Eunice R. Silva, Goreti Sales, Rui Henrique and Carmen Jerónimo

Int. J. Mol. Sci. 2021, 22(6), 3267; https://doi.org/10.3390/ijms22063267 - 23 Mar 2021

Cited by 15 | Viewed by 4375

Abstract

Secreted extracellular vesicles (EVs) are heterogeneous cell-derived membranous granules which carry a large diversity of molecules and participate in intercellular communication by transferring these molecules to target cells by endocytosis. In the last decade, EVs’ role in several pathological conditions, from etiology to [...] Read more.

Secreted extracellular vesicles (EVs) are heterogeneous cell-derived membranous granules which carry a large diversity of molecules and participate in intercellular communication by transferring these molecules to target cells by endocytosis. In the last decade, EVs’ role in several pathological conditions, from etiology to disease progression or therapy evasion, has been consolidated, including in central nervous system (CNS)-related disorders. For this review, we performed a systematic search of original works published, reporting the presence of molecular components expressed in the CNS via EVs, which have been purified from plasma, serum or cerebrospinal fluid. Our aim is to provide a list of molecular EV components that have been identified from both nonpathological conditions and the most common CNS-related disorders. We discuss the methods used to isolate and enrich EVs from specific CNS-cells and the relevance of its components in each disease context. Full article

(This article belongs to the Special Issue Role and Dynamics of Extracellular Vesicles in Central Nervous System Diseases)

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15 pages, 1568 KiB

Open AccessReview

Brain-Derived Extracellular Vesicles in Health and Disease: A Methodological Perspective

by Santra Brenna, Christoph Krisp, Hermann Clemens Altmeppen, Tim Magnus and Berta Puig

Int. J. Mol. Sci. 2021, 22(3), 1365; https://doi.org/10.3390/ijms22031365 - 29 Jan 2021

Cited by 19 | Viewed by 3974

Abstract

Extracellular vesicles (EVs) are double membrane structures released by presumably all cell types that transport and deliver lipids, proteins, and genetic material to near or distant recipient cells, thereby affecting their phenotype. The basic knowledge of their functions in healthy and diseased brain [...] Read more.

Extracellular vesicles (EVs) are double membrane structures released by presumably all cell types that transport and deliver lipids, proteins, and genetic material to near or distant recipient cells, thereby affecting their phenotype. The basic knowledge of their functions in healthy and diseased brain is still murky and many questions about their biology are unsolved. In neurological diseases, EVs are regarded as attractive biomarkers and as therapeutic tools due to their ability to cross the blood–brain barrier (BBB). EVs have been successfully isolated from conditioned media of primary brain cells and cerebrospinal fluid (CSF), but protocols allowing for the direct study of pathophysiological events mediated or influenced by EVs isolated from brain have only recently been published. This review aims to give a brief overview of the current knowledge of EVs’ functions in the central nervous system (CNS) and the current protocols to isolate brain-derived EVs (BDEVs) used in different publications. By comparing the proteomic analysis of some of these publications, we also assess the influence of the isolation method on the protein content of BDEVs. Full article

(This article belongs to the Special Issue Role and Dynamics of Extracellular Vesicles in Central Nervous System Diseases)

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29 pages, 1547 KiB

Open AccessReview

Synergistic Effects of Milk-Derived Exosomes and Galactose on α-Synuclein Pathology in Parkinson’s Disease and Type 2 Diabetes Mellitus

by Bodo C. Melnik

Int. J. Mol. Sci. 2021, 22(3), 1059; https://doi.org/10.3390/ijms22031059 - 21 Jan 2021

Cited by 30 | Viewed by 6191

Abstract

Epidemiological studies associate milk consumption with an increased risk of Parkinson’s disease (PD) and type 2 diabetes mellitus (T2D). PD is an α-synucleinopathy associated with mitochondrial dysfunction, oxidative stress, deficient lysosomal clearance of α-synuclein (α-syn) and aggregation of misfolded [...] Read more.

Epidemiological studies associate milk consumption with an increased risk of Parkinson’s disease (PD) and type 2 diabetes mellitus (T2D). PD is an α-synucleinopathy associated with mitochondrial dysfunction, oxidative stress, deficient lysosomal clearance of α-synuclein (α-syn) and aggregation of misfolded α-syn. In T2D, α-syn promotes co-aggregation with islet amyloid polypeptide in pancreatic β-cells. Prion-like vagal nerve-mediated propagation of exosomal α-syn from the gut to the brain and pancreatic islets apparently link both pathologies. Exosomes are critical transmitters of α-syn from cell to cell especially under conditions of compromised autophagy. This review provides translational evidence that milk exosomes (MEX) disturb α-syn homeostasis. MEX are taken up by intestinal epithelial cells and accumulate in the brain after oral administration to mice. The potential uptake of MEX miRNA-148a and miRNA-21 by enteroendocrine cells in the gut, dopaminergic neurons in substantia nigra and pancreatic β-cells may enhance miRNA-148a/DNMT1-dependent overexpression of α-syn and impair miRNA-148a/PPARGC1A- and miRNA-21/LAMP2A-dependent autophagy driving both diseases. MiRNA-148a- and galactose-induced mitochondrial oxidative stress activate c-Abl-mediated aggregation of α-syn which is exported by exosome release. Via the vagal nerve and/or systemic exosomes, toxic α-syn may spread to dopaminergic neurons and pancreatic β-cells linking the pathogenesis of PD and T2D. Full article

(This article belongs to the Special Issue Role and Dynamics of Extracellular Vesicles in Central Nervous System Diseases)

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20 pages, 12564 KiB

Open AccessReview

Extracellular Vesicles in CNS Developmental Disorders

by Ana Rita Gomes, Nasim Bahram Sangani, Tiago G. Fernandes, M. Margarida Diogo, Leopold M. G. Curfs and Chris P. Reutelingsperger

Int. J. Mol. Sci. 2020, 21(24), 9428; https://doi.org/10.3390/ijms21249428 - 11 Dec 2020

Cited by 23 | Viewed by 5739

Abstract

The central nervous system (CNS) is the most complex structure in the body, consisting of multiple cell types with distinct morphology and function. Development of the neuronal circuit and its function rely on a continuous crosstalk between neurons and non-neural cells. It has [...] Read more.

The central nervous system (CNS) is the most complex structure in the body, consisting of multiple cell types with distinct morphology and function. Development of the neuronal circuit and its function rely on a continuous crosstalk between neurons and non-neural cells. It has been widely accepted that extracellular vesicles (EVs), mainly exosomes, are effective entities responsible for intercellular CNS communication. They contain membrane and cytoplasmic proteins, lipids, non-coding RNAs, microRNAs and mRNAs. Their cargo modulates gene and protein expression in recipient cells. Several lines of evidence indicate that EVs play a role in modifying signal transduction with subsequent physiological changes in neurogenesis, gliogenesis, synaptogenesis and network circuit formation and activity, as well as synaptic pruning and myelination. Several studies demonstrate that neural and non-neural EVs play an important role in physiological and pathological neurodevelopment. The present review discusses the role of EVs in various neurodevelopmental disorders and the prospects of using EVs as disease biomarkers and therapeutics. Full article

(This article belongs to the Special Issue Role and Dynamics of Extracellular Vesicles in Central Nervous System Diseases)

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18 pages, 1277 KiB

Open AccessReview

The Role of Extracellular Vesicles in Demyelination of the Central Nervous System

by José Antonio López-Guerrero, Inés Ripa, Sabina Andreu and Raquel Bello-Morales

Int. J. Mol. Sci. 2020, 21(23), 9111; https://doi.org/10.3390/ijms21239111 - 30 Nov 2020

Cited by 9 | Viewed by 4703

Abstract

It is being increasingly demonstrated that extracellular vesicles (EVs) are deeply involved in the physiology of the central nervous system (CNS). Processes such as synaptic activity, neuron-glia communication, myelination and immune response are modulated by EVs. Likewise, these vesicles may participate in many [...] Read more.

It is being increasingly demonstrated that extracellular vesicles (EVs) are deeply involved in the physiology of the central nervous system (CNS). Processes such as synaptic activity, neuron-glia communication, myelination and immune response are modulated by EVs. Likewise, these vesicles may participate in many pathological processes, both as triggers of disease or, on the contrary, as mechanisms of repair. EVs play relevant roles in neurodegenerative disorders such as Alzheimer’s or Parkinson’s diseases, in viral infections of the CNS and in demyelinating pathologies such as multiple sclerosis (MS). This review describes the involvement of these membrane vesicles in major demyelinating diseases, including MS, neuromyelitis optica, progressive multifocal leukoencephalopathy and demyelination associated to herpesviruses. Full article

(This article belongs to the Special Issue Role and Dynamics of Extracellular Vesicles in Central Nervous System Diseases)

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9 pages, 727 KiB

Open AccessReview

A Brief History of Adherons: The Discovery of Brain Exosomes

by David Schubert

Int. J. Mol. Sci. 2020, 21(20), 7673; https://doi.org/10.3390/ijms21207673 - 16 Oct 2020

Cited by 7 | Viewed by 2600

Abstract

Although exosomes were first described in reticulocytes in 1983, many people do not realize that similar vesicles had been studied in the context of muscle and nerve, beginning in 1980. At the time of their discovery, these vesicles were named adherons, and they [...] Read more.

Although exosomes were first described in reticulocytes in 1983, many people do not realize that similar vesicles had been studied in the context of muscle and nerve, beginning in 1980. At the time of their discovery, these vesicles were named adherons, and they were found to play an important role in both cell–substrate and cell–cell adhesion. My laboratory described several molecules that are present in adherons, including heparan sulfate proteoglycans (HSPGs) and purpurin. HSPGs have since been shown to play a variety of key roles in brain physiology. Purpurin has a number of important functions in the retina, including a role in nerve cell differentiation and regeneration. In this review, I discuss the discovery of adherons and how that led to continuing studies on their role in the brain with a particular focus on HSPGs. Full article

(This article belongs to the Special Issue Role and Dynamics of Extracellular Vesicles in Central Nervous System Diseases)

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23 pages, 2332 KiB

Open AccessReview

Emerging Role of Extracellular Vesicles in the Pathophysiology of Multiple Sclerosis

by Ettore Dolcetti, Antonio Bruno, Livia Guadalupi, Francesca Romana Rizzo, Alessandra Musella, Antonietta Gentile, Francesca De Vito, Silvia Caioli, Silvia Bullitta, Diego Fresegna, Valentina Vanni, Sara Balletta, Krizia Sanna, Fabio Buttari, Mario Stampanoni Bassi, Diego Centonze and Georgia Mandolesi

Int. J. Mol. Sci. 2020, 21(19), 7336; https://doi.org/10.3390/ijms21197336 - 4 Oct 2020

Cited by 44 | Viewed by 5753

Abstract

Extracellular vesicles (EVs) represent a new reality for many physiological and pathological functions as an alternative mode of intercellular communication. This is due to their capacity to interact with distant recipient cells, usually involving delivery of the EVs contents into the target cells. [...] Read more.

Extracellular vesicles (EVs) represent a new reality for many physiological and pathological functions as an alternative mode of intercellular communication. This is due to their capacity to interact with distant recipient cells, usually involving delivery of the EVs contents into the target cells. Intensive investigation has targeted the role of EVs in different pathological conditions, including multiple sclerosis (MS). MS is a chronic inflammatory and neurodegenerative disease of the nervous system, one of the main causes of neurological disability in young adults. The fine interplay between the immune and nervous systems is profoundly altered in this disease, and EVs seems to have a relevant impact on MS pathogenesis. Here, we provide an overview of both clinical and preclinical studies showing that EVs released from blood–brain barrier (BBB) endothelial cells, platelets, leukocytes, myeloid cells, astrocytes, and oligodendrocytes are involved in the pathogenesis of MS and of its rodent model experimental autoimmune encephalomyelitis (EAE). Most of the information points to an impact of EVs on BBB damage, on spreading pro-inflammatory signals, and altering neuronal functions, but EVs reparative function of brain damage deserves attention. Finally, we will describe recent advances about EVs as potential therapeutic targets and tools for therapeutic intervention in MS. Full article

(This article belongs to the Special Issue Role and Dynamics of Extracellular Vesicles in Central Nervous System Diseases)

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26 pages, 940 KiB

Open AccessReview

Extracellular Vesicles as Innovative Tool for Diagnosis, Regeneration and Protection against Neurological Damage

by Pavle Andjus, Maja Kosanović, Katarina Milićević, Mukesh Gautam, Seppo J. Vainio, Denis Jagečić, Elena N. Kozlova, Augustas Pivoriūnas, Juan-Carlos Chachques, Mirena Sakaj, Giulia Brunello, Dinko Mitrecic and Barbara Zavan

Int. J. Mol. Sci. 2020, 21(18), 6859; https://doi.org/10.3390/ijms21186859 - 18 Sep 2020

Cited by 59 | Viewed by 8007

Abstract

Extracellular vesicles (EVs) have recently attracted a great deal of interest as they may represent a new biosignaling paradigm. According to the mode of biogenesis, size and composition, two broad categories of EVs have been described, exosomes and microvesicles. EVs have been shown [...] Read more.

Extracellular vesicles (EVs) have recently attracted a great deal of interest as they may represent a new biosignaling paradigm. According to the mode of biogenesis, size and composition, two broad categories of EVs have been described, exosomes and microvesicles. EVs have been shown to carry cargoes of signaling proteins, RNA species, DNA and lipids. Once released, their content is selectively taken up by near or distant target cells, influencing their behavior. Exosomes are involved in cell–cell communication in a wide range of embryonic developmental processes and in fetal–maternal communication. In the present review, an outline of the role of EVs in neural development, regeneration and diseases is presented. EVs can act as regulators of normal homeostasis, but they can also promote either neuroinflammation/degeneration or tissue repair in pathological conditions, depending on their content. Since EV molecular cargo constitutes a representation of the origin cell status, EVs can be exploited in the diagnosis of several diseases. Due to their capability to cross the blood–brain barrier (BBB), EVs not only have been suggested for the diagnosis of central nervous system disorders by means of minimally invasive procedures, i.e., “liquid biopsies”, but they are also considered attractive tools for targeted drug delivery across the BBB. From the therapeutic perspective, mesenchymal stem cells (MSCs) represent one of the most promising sources of EVs. In particular, the neuroprotective properties of MSCs derived from the dental pulp are here discussed. Full article

(This article belongs to the Special Issue Role and Dynamics of Extracellular Vesicles in Central Nervous System Diseases)

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22 pages, 305 KiB

Open AccessReview

Role of Extracellular Vesicles in Substance Abuse and HIV-Related Neurological Pathologies

by Katherine E. Odegaard, Subhash Chand, Sydney Wheeler, Sneham Tiwari, Adrian Flores, Jordan Hernandez, Mason Savine, Austin Gowen, Gurudutt Pendyala and Sowmya V. Yelamanchili

Int. J. Mol. Sci. 2020, 21(18), 6765; https://doi.org/10.3390/ijms21186765 - 15 Sep 2020

Cited by 10 | Viewed by 4742

Abstract

Extracellular vesicles (EVs) are a broad, heterogeneous class of membranous lipid-bilayer vesicles that facilitate intercellular communication throughout the body. As important carriers of various types of cargo, including proteins, lipids, DNA fragments, and a variety of small noncoding RNAs, including miRNAs, mRNAs, and [...] Read more.

Extracellular vesicles (EVs) are a broad, heterogeneous class of membranous lipid-bilayer vesicles that facilitate intercellular communication throughout the body. As important carriers of various types of cargo, including proteins, lipids, DNA fragments, and a variety of small noncoding RNAs, including miRNAs, mRNAs, and siRNAs, EVs may play an important role in the development of addiction and other neurological pathologies, particularly those related to HIV. In this review, we summarize the findings of EV studies in the context of methamphetamine (METH), cocaine, nicotine, opioid, and alcohol use disorders, highlighting important EV cargoes that may contribute to addiction. Additionally, as HIV and substance abuse are often comorbid, we discuss the potential role of EVs in the intersection of substance abuse and HIV. Taken together, the studies presented in this comprehensive review shed light on the potential role of EVs in the exacerbation of substance use and HIV. As a subject of growing interest, EVs may continue to provide information about mechanisms and pathogenesis in substance use disorders and CNS pathologies, perhaps allowing for exploration into potential therapeutic options. Full article

(This article belongs to the Special Issue Role and Dynamics of Extracellular Vesicles in Central Nervous System Diseases)

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19 pages, 903 KiB

Open AccessReview

HIV Associated Risk Factors for Ischemic Stroke and Future Perspectives

by Saifudeen Ismael, Mohammad Moshahid Khan, Prashant Kumar, Sunitha Kodidela, Golnoush Mirzahosseini, Santhosh Kumar and Tauheed Ishrat

Int. J. Mol. Sci. 2020, 21(15), 5306; https://doi.org/10.3390/ijms21155306 - 26 Jul 2020

Cited by 14 | Viewed by 6667

Abstract

Although retroviral therapy (ART) has changed the HIV infection from a fatal event to a chronic disease, treated HIV patients demonstrate high prevalence of HIV associated comorbidities including cardio/cerebrovascular diseases. The incidence of stroke in HIV infected subjects is three times higher than [...] Read more.

Although retroviral therapy (ART) has changed the HIV infection from a fatal event to a chronic disease, treated HIV patients demonstrate high prevalence of HIV associated comorbidities including cardio/cerebrovascular diseases. The incidence of stroke in HIV infected subjects is three times higher than that of uninfected controls. Several clinical and postmortem studies have documented the higher incidence of ischemic stroke in HIV infected patients. The etiology of stroke in HIV infected patients remains unknown; however, several factors such as coagulopathies, opportunistic infections, vascular abnormalities, atherosclerosis and diabetes can contribute to the pathogenesis of stroke. In addition, chronic administration of ART contributes to the increased risk of stroke in HIV infected patients. Concurrently, experimental studies in murine model of ischemic stroke demonstrated that HIV infection worsens stroke outcome, increases blood brain barrier permeability and increases neuroinflammation. Additionally, residual HIV viral proteins, such as Trans-Activator of Transcription, glycoprotein 120 and Negative regulatory factor, contribute to the pathogenesis. This review presents comprehensive information detailing the risk factors contributing to ischemic stroke in HIV infected patients. It also outlines experimental evidence demonstrating the impact of HIV infection on stroke outcomes, in addition to possible novel therapeutic approaches to improve these outcomes. Full article

(This article belongs to the Special Issue Role and Dynamics of Extracellular Vesicles in Central Nervous System Diseases)

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