The Link Among Neurological Diseases: Extracellular Vesicles as a Possible Brain Injury Footprint


Fausta Ciccocioppoa,b    Paola Lanutia,b    Diego Centonzec,d    Sebastiano Misciaa,b    

Marco Marchisioa,b


aDepartment of Medicine and Aging Sciences, University “G. D’Annunzio” Chieti-Pescara, Chieti, bCenter on Aging Science and Translational Medicine (Ce.S.I.-Me.T.), University “G. D’Annunzio” Chieti-Pescara, Chieti, cLaboratory of Synaptic Immunopathology, Department of Systems Medicine, Tor Vergata University, Rome, Italy, dUnit of Neurology, IRCCS Neuromed, Pozzilli, (IS), Italy





Key Words

Extracellular Vesicles • Neurodegenerative Diseases • Multiple Sclerosis • Stroke • Brain Tumours



Extracellular vesicles (EVs), referred as membranous vesicles released into body fluids from all cell types, represent a novel model to explain some aspects of the inter-cellular cross talk. It has been demonstrated that the EVs modify the phenotype of target cells, acting through a large spectrum of mechanisms. In the central nervous system, the EVs are responsible of the wide range of physiological processes required for normal brain function and neuronal support, such as immune signaling, cellular proliferation, differentiation, and senescence. Growing evidences link the EV functions to the pathogenic machinery of the neurological diseases, contributing to the disease progression and spreading. Extracellular vesicles are involved in the brain injury by multimodal ways; they propagate inflammation across the blood brain barrier (BBB), mediate neuroprotection and modulate regenerative processes. For these reasons, extracellular vesicles represent a promising biomarker in neurological disorders as well as an interesting starting point for the development of novel therapeutic strategies. Herein, we review the role of the EVs in the pathogenesis of neurological disease, discussing their potential clinical applications.





The term ‘‘extracellular vesicles’’ (EVs) refers to membrane-surrounded vesicles, that, together with metabolite solutions, ions, proteins and polysaccharides makes up the extracellular milieu. Growing evidences have proposed the EVs as novel mediators of the inter-cellular cross talk. Extracellular vesicles determine the modification of the phenotype of target cells, acting through a large spectrum of mechanisms [1]. They represent specific ‘packages’ containing different bioactive materials, such as cytosolic and membrane proteins, mRNAs, non-coding RNAs, and even DNA fragments [2]. Extracellular vesicles are released virtually from all cell types and represent multimodal signaling vehicles able to travel wide range of distances in many body fluids. As a matter of fact, the EVs have been found in the peripheral blood, in the milk, in the saliva, in the cerebrospinal fluid (CSF), in the tears and in the urine, where they carry specific biological messages [3–5]. Extracellular vesicles, can be categorized as exosomes, activation- or apoptosis-induced microvesicles (MVs)/microparticles and apoptotic bodies, based on their biogenesis and their size [6]. However, they also include other vesicular structures originating from plasma membranes, such as exosome-like vesicles that lack lipid raft micro-domains and membrane particles [7, 8].

Exosomes are small vesicles (approximately 50 – 100 nm in diameter) surrounded by a phospholipid bilayer, released by exocytosis of multivesicular bodies (MVBs) [9]. They expose phosphatidylserine on their surfaces, and CD63, CD81, CD9, LAMP1 and TSG101 are considered common exosome markers [6]. Exosomes exert their biological functions by different ways, including direct surface contact between the EVs and the target cells, the endocytosis, the EV-cell membrane fusion and the horizontal transfer of the mRNA/miRNA, the oncogenic receptors and the HIV particles [10–13]. Exosomes have been largely described both as mediators of the immune cell functions (involving dendritic, T and B cells, as well as macrophages), as well as regulators of the tumor mechanisms, where their key role is linked to presentation of the antigen and to immunomodulatory activity [10, 14].

Microvesicles have been predominantly described as platelets, endothelial and red blood cells products. Their diameters measure 100 – 1, 000 nm [10, 15], and are surrounded by a phospholipid bilayer that may or not expose phosphatidylserine on the membrane surface [16]. The regulated release of the MVs, by budding/blabbing of the plasma membrane, is induced upon the activation of cell surface receptors. Microvesicles have pro-coagulant functions and represent a form of secretion for the IL1b. The role of the MVs has been also described in the pathogenesis of rheumatoid arthritis, in the mechanisms associated to tumor pro-invasive characteristics, and in the induction of oncogenic cellular transformation and feto-maternal communication [6].

Apoptotic Bodies are approximately 1 – 5 µm in diameter; they are released as blebs from cells undergoing apoptosis and are characterized by phosphatidylserine externalization [17, 18]. Apoptotic bodies horizontally transfer oncogenes and/or DNA, are involved in the presentation of the T cell epitopes upon their uptake by phagocytic cells and in the representation of the B cell autoantigens [6].

Regardless of differences mentioned above, the terms of the “EVs”, “microvesicles” and “exosomes” have been interchangeably used in the literature, therefore, confounding the evaluation of obtained results. However, given that EVs are characterized by small size, the EV detection require several pre-analytical enrichment steps (i.e. the centrifugation/ultracentrifugation, the ultrafiltration, the size exclusion chromatography, the immunocapture, the hydrostatic dialysis or the hydrostatic filtration dialysis (HFD). For these reasons, their final characterization uses highly manipulated material [19, 20]. In this context, the final measurement may not reflect the initial characteristics of the samplest [21]. For this reasons, several working-groups composed by experts in the field, are studying standardization methods for the EV clear identification and analysis [22, 23].



Physiological role of EVs in the Central Nervous System


In the Central Nervous System (CNS), the EVs have been involved in the rich network of intercellular connections responsible for the maintenance of the physiological homeostasis as well as for the development of the pathogenic machinery leading to neurological diseases (neurodegenerative disorders, as well as brain tumors and stroke).

It has been demonstrated that the EVs released by neurons and glial cells are able to pass across the brain blood barrier (BBB), through a mechanism known as trans-cytosis [24, 37, 40]. This allows the systemic propagation of physio-pathological information; the EVs have been proposed, therefore, as peripheral biomarker candidates for neurological diseases [25-27] (Fig. 1). Extracellular vesicle biogenesis give rise to their specific cargo packaging, which is strictly related both to the characteristics of their relative parental cells and to the stimulus which has determined their release [27]. It has been shown, that microglial-derived EVs expose CD13 and monocarboxylate transporter 1 [28], the neural-derived EVs move the cell adhesion molecule L1, the GPI-anchored prion protein and the subunits of glutamate receptors [29]; while the astrocyte-derived exosomes carry functional glutamate transporters and mitochondrial DNA [30, 31]. In addition, the oligodendrocytic-derived exosomes transport myelin and associated lipids [32]. As already underlined, the content of the EV depends on the stimulus received. It is known that several mechanisms, such as the synaptic activity, the depolarization, the function of sphingolipid-metabolizing enzymes and the PARK9 influence the release of exosomes from neurons [29, 33–35]. On the other hand, the serotonin-Wnt3a and the neurotransmitter glutamate regulate the EV production from microglia and oligodendrocytes, respectively [36-38].


Fig. 1. Extracellular Vesicle' Origin, Cargo and Clinical Applications. Extracellular Vesicles secreted by neurons and glial cells are able to cross the brain blood barrier (BBB) through a mechanism known as trans-cytosis and their impact on target cells depends by the cargo that they shuttle. Thus, the EVs could represent a diagnostic and functional biomarker as well as suitable therapeutic agents in neurological diseases. Source: Servier Medical Art by Servier and modified under the following terms: Creative Commons Attribution 3.0 Unported license (CC BY 3.0).


Extracellular vesicles are also responsible of several physiological processes required for normal brain functions and neuronal support, including immune signaling, cellular proliferation, differentiation, and senescence [39-41]. The EVs transfer synaptic proteins, mRNAs and miRNAs, therefore allowing the cell-to-cell communication, modulating functions and phenotypes of target cells [42, 43]. Extracellular vesicles are also involved in the clearance of the unwanted materials and cellular waste [22]. Moreover, they show a key role in the synaptic activity [29, 38, 44], as well as in promoting neuroprotection and regeneration in brain diseases [45–48].

The neuron–glia cross-talk EV-mediated appears linked to synaptic functions, to neurovascular integrity and to myelination in the CNS. It has been demonstrated that the EVs carry several proteins linked to synaptic plasticity mechanisms, such as the a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor components and the trafficking protein Evi/Wntless, involved in the formation of synaptic buttons [29, 35, 49–52]. Extracellular vesicles are also involved in the brain vascular integrity maintenance through the transfer of the miR-132 into endothelial cells, followed by the upregulation of the adherent junction protein Cdh5 expression [53]. In addition, acting through a Rho-associated coiled-coil protein kinase (ROCK) activation and regulation of actomyosin contractility, the EVs are involved in myelination and re-myelination processes [54]. Extracellular vesicles convey miR-219 into oligodendrocyte precursor cells (OPC) increasing the OPC numbers and their myelin production, thereby repressing the expression of negative regulators of myelination [55–57]. The glial-originated EVs appear to offer neuron support, providing a regulatory feedback on presynaptic activity, both in the excitatory and the inhibitory neurotransmission [50]. The neuronal internalization of the oligodendrocyte-derived EVs [58], leads to functional cargo recovery and to genetic modulations of the specific plasticity-related targets, such as the VGF nerve growth factor inducible (VGF) and the brain-derived neurotrophic factor (BDNF) [38, 59]. On the other hand, the microglial-secreted EVs lead to increased presynaptic release of neurotransmitters, through a stimulation of the neuronal sphingolipid metabolism the amplifies the excitatory neurotransmission [44, 60]. The glial EVs have been shown to also carry several enzymes, supporting the neuronal energy metabolism [28, 32, 61].





Emerging concepts propose the EVs as key mediators in the information network linked to the pathogenic machinery of the neurological diseases. Extracellular vesicles are involved in the brain injury through multimodal ways; they propagate inflammation across the BBB, but also mediate neuroprotection and modulate regenerative processes. The EV-mediated signaling appears to support neuronal survival during ischemic stress [62], it is also linked to brain cancer progression [63] and contributes to protein aggregation processes and clearance in neurodegenerative diseases [50]. In Table 1 we have resumed the EV roles in neurological disorders.


Table 1. The Extracellular Vesicles' Roles in Neurological Disorders


Neurodegenerative Diseases

Neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD) and Amyotrophic Lateral Sclerosis (ALS) represent relevant issues for public health. In the aforementioned pathologies the lack of preclinical biomarkers for the identification of the early stages of the toxic protein aggregation processes makes impossible the administration of specific treatments to control the iceberg pathogenic machinery [64–66]. According to these reasons, the research focuses its interest on the EVs as potential source of information in early pathological disease stages Extracellular vesicles could represent diagnostic and functional biomarkers as well as suitable therapeutic agents in neurodegenerative diseases, allowing the monitoring of the pathogenic status in real time [67]. Recent literature describes the EV shuttle role in the spreading of misfolded proteins through a prion like mechanism in the cerebral “proteinopathies”, such as the b-amyloid (Ab) and the tau protein in AD, the a-synuclein protein in PD and the TDP-43 in ALS [68–70]. The gene alteration, the protein translation, the lysosomal dysfunction and the RNA transfer promote the misfolded protein shuttle from a “diseased cell” to a “healthy cell target” producing aggregation and accumulation of the misfolded protein in the target recipient cells [71, 72]. In the Parkinson's disease, the cellular overexpression and the aggregation of a-synuclein in Lewy bodies and Lewy neurites result linked to increased transport of a-synuclein via EV [73]. In this contest, the lysosomal dysfunction is involved in the cell-to-cell transmission of a-synuclein oligomers packaged in the EVs, representing a second attempt to prevent toxic protein accumulation [74]. Recent studies on the SH-SY5Y cells have described that the a-synuclein is conveyed via exosomes [75], providing the catalytic conditions for nucleation and toxic misfolded protein accumulation [76]. It has been shown that the CSF level of a-synuclein protein packaged in EVs is straightly related to the cognitive impairment in the PD patients [77]. Furthermore, additional data reinforced the hypothesis that the EVs could referee the neurodegenerative machinery by increasing the induction of specific apoptotic pathways [63, 78]. Similarly, the Ab protein is a proteolytic product of the amyloid precursor protein (APP), which is sequentially cleaved by secretase (BACE1) and the gamma-secretase complex; its aggregation and the related toxic accumulation has been implicated in the Alzheimer's disease neuropathology [67]. According to the current view, it has been suggested that the EVs represent a multimodal way for the spreading of the Ab and Tau neuropathology among neurons [79–81]. The evidence that the Ab peptides (i.e. APP, APPC terminal fragments, APP intra-cellular domain, Ab) are exosomes-associated, together with the evidence that some typical exosome proteins (e.g., flotillins, Alix) have been found in the amyloid plaques, could explain the plaque formation in the AD brain [67, 82–84]. However, the role of the EVs in AD is controversial. In such a context, several data have described that the EVs mediate Ab neurotoxicity by neutralizing the expression of the surface proteins in the EVs [85].  It has been also described that the EVs play a key role as scavengers of neurotoxic Ab. In the mouse model of the Alzheimer's disease, after the intracerebral inoculation of the neuronal-derived EV [86] that contain in glycosphingolipids bound the neurotoxic Ab, the microglial-derived EVs are involved in the Ab clearance and, lastly, the Ab pathology resulted decreased [34, 68]. Furthermore, data show that the EVs could contribute to mitochondrial dysfunction, spreading neuronal injury in the Alzheimer's disease brains [87].

Extracellular vesicles involvement has been demonstrated also in the Amyotrophic Lateral Sclerosis, a neurodegenerative disease associated to SOD1 gene mutations and characterized by motor neurons degeneration. It has been shown that, in the ALS cellular models, the spread of the misfolded SOD1 protein could be associated to prion-like transmission mechanisms modulated by EVs [88, 89]. An additional misfolded protein in the ALS is the TAR DNA-binding protein of 43 kDa (TDP-43), which represents the major neuropathological hallmark in the Amyotrophic Lateral Sclerosis brain inclusions [90]. Aggregates of the TDP43 are packaged in the EVs and they have detected in the body fluids [91]. Extracellular vesicles also enclose the RNA transcripts, such as piRNA, miRNA and tRNA, conveyed to the microenvironment and/or to long distances [92-95]. Thus, the EVs mediate both inter-cellular communication between cells and trans-cellular communication between brain and distant organs [10, 96]. Therefore, the small RNA transcripts, released by EVs into biological fluids, exert specific biological effects on target cells, modulating gene expressions [97–99]. Deregulation of the miRNAs has been described in the neurodegenerative disorders; it has been demonstrated that the miR-132 and the miR-212 are down-regulated in Alzheimer's disease and in Fronto-Temporal Dementia brain tissues [100-104]. Thus, specific dysregulated microRNAs conveyed by the EVs in the CSF could be able to distinguish different neurodegenerative disorders [105, 106]. The whole of these surprising evidences remark, in vivo, the multimodal way through which the EVs modulate the spread of neuropathological features in different neurodegenerative disorders.


Multiple Sclerosis

Multiple sclerosis (MS) is the most common immune-mediated inflammatory demyelinating disease, in the central nervous system, associated to autoreactive lymphocyte action leading to inflammation, demyelination and axonal degeneration [107, 108].

In reason of the ascertained role of the extracellular vesicles in immunomodulation, their involvement in MS results highly intriguing, representing one of the first neurological disorders in which the EVs have been detected. In particular, the involvement of the oligodendrocyte-derived EVs and the endothelium-derived EVs in the activation of the CD4+ and the CD8+ lymphocytes in the CSF of the MS patients has been described [109, 110]. The additional data underlined increased numbers of the myeloid-derived EVs in the CFS from the MS patients and proposed their positive modulator role on the excitatory transmission [44, 63, 111].

In the plasma samples of the MS patients, higher levels of the endothelium-derived EVs have been found and significant increase of the CD31-expressing EVs was evidenced during the acute phase in the MS patients; while higher levels of the CD51-expressing EVs were found both in remission and exacerbation phases, possibly reflecting the related acute vs chronic endothelium dysfunction status [112].

The endothelial-derived-EVs and the platelet-derived EVs result also increased in the Multiple sclerosis along with the elevation of CD62p expression, which is described as a platelets activation marker. In this contest, it has been described that the extracellular vesicles participate to the disruption of the BBB, increasing the permeability of endothelial layers in vitro [113–115] and promote the monocyte activation in the plasma, mediating the trans-endothelial recruitment of inflammatory cells [116].

Recent data have described the phenotypes of the EVs stemming from different cellular lineages (i.e. from leukocytes, monocytes and platelets), both in Multiple Sclerosis patients and healthy subjects.  The level of the all EV subsets resulted higher in relapsing-remitting patients than in the secondary progressive patients and controls, suggesting that the spreading of the extracellular vesicles could reflect the inflammatory vs the chronic degeneration status, respectively [117]. It has been described a linear correlation between the higher CSF level of the EVs in the MS patients and the gadolinium enhancing MRI lesions, index of acute phase in the natural history of disease [111]. In addition, recent data have described the RNA profile of the serum EVs in the MS subjects, characterizing four different peripheral EVs subsets, respect to their miRNA contents (i.e. hsa-miR-122-5p, hsa-miR-196b-5p, hsa-miR-301a-3p, hsa-miR-532-5p). Those miRNAs identified the MS patients respect to control subjects and the upregulation of the EVs conveying in the serum the miRNAs profile mentioned above resulted linked to the relapse phase of the disease as well as to a gadolinium enhancement on brain magnetic resonance imaging [67, 118]. According to the immunomodulation role of the EVs in the MS, several studies have been detected, in the serum of the pregnant MS woman, the EVs able to decrease T-cell activation, probably leading the well-known immune privileged status in the MS during pregnancy, and suggesting that EVs could modulate the diseases status [27, 119–121]. All in all, these findings recall in the mind the possible role of the EVs as biomarker of the immune status in the Multiple Sclerosis patients.



Stroke is a focal cerebral insult leading to death or severe neurological disability. Discovery of the biomarkers for cerebral vascular risk identification and stratification of the stroke patient represents a strong focus of interest. In the stroke pathology, the characterization of the EV profiles in vivo, could represent a powerful diagnostic and prognostic tool as well as an index of therapeutic response. Limited data are available on the use of the EVs as biomarkers or as neuroprotective treatment in stroke [27, 122]. A recent study has described the faster cognitive decline of stroke patients respect to healthy subjects, beyond than the subacute phase, and also to 6 years after the stroke incident was happened [123]. In this case, EVs could act as mediators and/or shuttles of functional biomarkers, providing novel potential diagnostic approaches for the improvement of the cognitive dysfunction management after stroke event [27]. Literature have proposed the mRNA profiles as a potential diagnostic biomarkers of the stroke. Nevertheless, the mRNA profiles showed a good sensibility but reduced specificity to discriminate other disorders, such as cardiovascular risk factors, hypoglycemia, myocardial infarction or hemorrhagic stroke from ischemic stroke [27, 122].

Of note, some differentially regulated miRNAs have been associated to stroke severity and outcome in the plasma of patients and in the animal models of stroke [124]. The latter showed the involvement of the miR-133b, conveyed by the stromal-derived EVs, in neural structure modification [105, 125]. It has also been demonstrated that along with miRNAs, also the monitoring of different proteins, such as the MMP-9, the S100β, the ICAM1 and the GFAP represent potentially useful diagnostic biomarkers in stroke [122, 126]. The investigations of the miRNA, the mRNA or the protein cargoes in the EVs profile could open novel diagnostic, prognostic and therapeutic perspectives in stroke [27].


Brain Tumors

Common processes linked to disease initiation and spread (i.e. genetic and epigenetic features, hypoxic environment exposure, mutagens and senescence factors) have been described for neurodegenerative diseases and brain cancers. Growing studies describe a network of the EVs-mediated cellular interactions, which are strictly linked to cancer advancement [63]. As matter of fact, the tumor-derived EVs release soluble factors and mediate signaling machineries related to dysregulated cell growth and hypoxic environment development [127]. Furthermore, proteins as onco-proteins, ephrins and chemokine receptors, but also DNA, mRNAs, miRNAs and other small noncoding RNAs are packaged into the cancer-derived EVs [12, 128–132]. In line with their immunomodulatory role, the extracellular vesicles stemming from primary tumor cells result involved in the immune system inhibition as well as in development of the responsive environment for metastasis in the cancer machinery [133]. In addition, just as in neurodegenerative diseases, also in cancer progression, has been described a prion-like model, in which cancer cells-derived EVs induce tumor promoting effects in nearby cells [70]. The viruses-derived EVs, known to be linked to certain cancers, such as human papillomavirus (HPV), human immuno- deficiency virus (HIV), and human T cell lymphotropic (T cell leukemia/lymphoma) virus (HTLV)-1, could spread the pathology trough an EVs-dependent mechanisms [70, 134]. In this contest, glioblastoma-derived EVs promoted the proliferation of cultured cells from which they were originated [130, 135] and when they are put into co-cultured with endothelial cells induce the alteration in gene expression and angiogenesis, through the modulation of endothelial cells [70, 127, 129, 136]. All these evidences, underline the involvement of the EVs in cancer physiopathology and their potential use in the prognostic and therapeutic monitoring.





All in all, these data underline that circulating EVs could be proposed as reliable biomarkers, representing an intriguing starting point for the development of novel therapeutic strategies, based on EV modulation. However, in this scenario, the limit of the translation of the EV analysis into the clinical practice come from different highly discussed questions, yet not solved, in this field. First of all, the heterogeneous EV nomenclature available in current literature determines a real problem when data have to be compared and reproduced [137]. Also, it must be taken into account that the EV detection presents enormous technological issues and also their biological roles are nowadays not fully characterized [1, 19]. In particular, the ideal method should detect EV larger than 50 nm and larger directly from fresh body fluids. It has to rely on a technique able to determine the concentration, as well as the phenotype of EVs being able to identify also the smallest EV compartment [19]. Therefore, further efforts need to be planned to improve those lacking points, in order to measure the real power of the extracellular vesicles as a novel tool in neurological diseases.





This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. FC drafted the manuscript. PL, DC, SM and MM critically edited the manuscript.



Disclosure Statement


The authors have no ethical and/or conflicts of interest to declare. The datasets generated during and/or analyzed during the current study are available in the reference list. All authors read and approved the final manuscript.





1 Colombo M, Raposo G, Théry C :Biogenesis, Secretion, and Intercellular Interactions of Exosomes and Other Extracellular Vesicles. Annu Rev Cell Dev Biol 2014;30:255-289.
PMID: 25288114


2 Takahashi A, Okada R, Nagao K, Kawamata Y, Hanyu A, Yoshimoto S, Takasugi M, Watanabe S, Kanemaki MT, Obuse C, Hara E: Exosomes maintain cellular homeostasis by excreting harmful DNA from cells. Nat Commun 2017;8:15287.
PMID: 28508895 PMCid:PMC5440838


3 Keller S, Ridinger J, Rupp A-K, Janssen JWG, Altevogt P: Body fluid derived exosomes as a novel template for clinical diagnostics. J Transl Med 2011;9:86.
PMID: 21651777 PMCid:PMC3118335


4 Pieragostino D, Cicalini I, Lanuti P, Ercolino E, di Ioia M, Zucchelli M, Zappacosta R, Miscia S, Marchisio M, Sacchetta P, Onofrj M, Del Boccio P: Enhanced release of acid sphingomyelinase-enriched exosomes generates a lipidomics signature in CSF of Multiple Sclerosis patients. Sci Rep 2018;8:3071.
PMID: 29449691 PMCid:PMC5814401


5 Pipino C, Mandatori D, Buccella F, Lanuti P, Preziuso A, Castellani F, Grotta L, Di Tomo P, Marchetti S, Di Pietro N, Cichelli A, Pandolfi A, Martino G: Identification and Characterization of a Stem Cell-Like Population in Bovine Milk: A Potential New Source for Regenerative Medicine in Veterinary. Stem Cells Dev 2018;27:1587-1597.
PMID: 30142991


6 György B, Szabó TG, Pásztói M, Pál Z, Misják P, Aradi B, László V, Pállinger É, Pap E, Kittel Á, Nagy G, Falus A, Buzás EI: Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci 2011;68:2667-2688.
PMID: 21560073 PMCid:PMC3142546


7 Islam A, Jones H, Hiroi T, Lam J, Zhang J, Moss J, Vaughan M, Levine SJ: cAMP-dependent Protein Kinase A (PKA) Signaling Induces TNFR1 Exosome-like Vesicle Release via Anchoring of PKA Regulatory Subunit RIIβ to BIG2. J Biol Chem 2008;283:25364-25371.
PMID: 18625701 PMCid:PMC2533074


8 Marzesco A-M, Janich P, Wilsch-Bräuninger M, Dubreuil V, Langenfeld K, Corbeil D, Huttner WB: Release of extracellular membrane particles carrying the stem cell marker prominin-1 (CD133) from neural progenitors and other epithelial cells. J Cell Sci 2005;118:2849-2858.
PMID: 15976444


9 Hurley JH, Boura E, Carlson LA, Różycki B: Membrane budding. Cell 2010;143:875-887.
PMID: 21145455 PMCid:PMC3102176


10 Théry C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses: Nat Rev Immunol 2009;9:581-93.
PMID: 19498381


11 Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO: Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007;9:654-659.
PMID: 17486113


12 Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L, Guha A, Rak J: Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol 2008;10:619-624.
PMID: 18425114


13 Izquierdo-Useros N, Naranjo-Gómez M, Archer J, Hatch SC, Erkizia I, Blanco J, Borrŕs FE, Puertas MC, Connor JH, Fernández-Figueras MT, Moore L, Clotet B, Gummuluru S, Martinez-Picado J: Capture and transfer of HIV-1 particles by mature dendritic cells converges with the exosome-dissemination pathway. Blood 2009;113:2732-2741.
PMID: 18945959 PMCid:PMC2661860


14 Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding C V, Melief CJ, Geuze HJ: B lymphocytes secrete antigen-presenting vesicles. J Exp Med 1996;183:1161-1172.
PMID: 8642258


15 György B, Módos K, Pállinger E, Pálóczi K, Pásztói M, Misják P, Deli MA, Sipos A, Szalai A, Voszka I, Polgár A, Tóth K, Csete M, Nagy G, Gay S, Falus A, Kittel A, Buzás EI: Detection and isolation of cell-derived microparticles are compromised by protein complexes resulting from shared biophysical parameters. Blood 2011;117:e39-e48.
PMID: 21041717


16 Connor DE, Exner T, Ma DDF, Joseph JE: The majority of circulating platelet-derived microparticles fail to bind annexin V, lack phospholipid-dependent procoagulant activity and demonstrate greater expression of glycoprotein Ib. Thromb Haemost 2010;103:1044-1052.
PMID: 20390225


17 Hristov M, Erl W, Linder S, Weber PC: Apoptotic bodies from endothelial cells enhance the number and initiate the differentiation of human endothelial progenitor cells in vitro. Blood 2004;104:2761-2766.
PMID: 15242875


18 Beyer C, Pisetsky DS: The role of microparticles in the pathogenesis of rheumatic diseases. Nat Rev Rheumatol 2010;6:21-29.
PMID: 19949432


19 Coumans FAW, Brisson AR, Buzas EI, Dignat-George F, Drees EEE, El-Andaloussi S, Emanueli C, Gasecka A, Hendrix A, Hill AF, Lacroix R, Lee Y, van Leeuwen TG, Mackman N, Mäger I, Nolan JP, van der Pol E, Pegtel DM, Sahoo S, Siljander PRM, et al.: Methodological Guidelines to Study Extracellular Vesicles. Circ Res 2017;120:1632-1648.
PMID: 28495994


20 van der Pol E, Coumans F, Varga Z, Krumrey M, Nieuwland R: Innovation in detection of microparticles and exosomes. J Thromb Haemost 2013;1:36-45.
PMID: 23809109


21 Lacroix R, Robert S, Poncelet P, Kasthuri RS, Key NS, Dignat-George F: Standardization of platelet-derived microparticle enumeration by flow cytometry with calibrated beads: results of the International Society on Thrombosis and Haemostasis SSC Collaborative workshop. J Thromb Haemost 2010;8:2571-2574.
PMID: 20831623


22 van der Pol E, Böing AN, Harrison P, Sturk A, Nieuwland R: Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol Rev 2012;64:676-705.
PMID: 22722893


23 Lötvall J, Hill AF, Hochberg F, Buzás EI, Di Vizio D, Gardiner C, Gho YS, Kurochkin I V, Mathivanan S, Quesenberry P, Sahoo S, Tahara H, Wauben MH, Witwer KW, Théry C: Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J Extracell Vesicles 2014;3:26913.
PMID: 25536934 PMCid:PMC4275645


24 Grapp M, Wrede A, Schweizer M, Hüwel S, Galla H-J, Snaidero N, Simons M, Bückers J, Low PS, Urlaub H, Gärtner J, Steinfeld R: Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma. Nat Commun 2013;4:2123.
PMID: 23828504


25 Dickens AM, Tovar-Y-Romo LB, Yoo SW, Trout AL, Bae M, Kanmogne M, Megra B, Williams DW, Witwer KW, Gacias M, Tabatadze N, Cole RN, Casaccia P, Berman JW, Anthony DC, Haughey NJ: Astrocyte-shed extracellular vesicles regulate the peripheral leukocyte response to inflammatory brain lesions. Sci Signal 2017;10:7696.
PMID: 28377412 PMCid:PMC5590230


26 Couch Y, Akbar N, Roodselaar J, Evans MC, Gardiner C, Sargent I, Romero IA, Bristow A, Buchan AM, Haughey N, Anthony DC: Circulating endothelial cell-derived extracellular vesicles mediate the acute phase response and sickness behaviour associated with CNS inflammation. Sci Rep 2017;7:9574.
PMID: 28851955 PMCid:PMC5575066


27 Kanninen KM, Bister N, Koistinaho J, Malm T: Exosomes as new diagnostic tools in CNS diseases. Biochim Biophys Acta 2016;1862:403-410.
PMID: 26432482


28 Potolicchio I, Carven GJ, Xu X, Stipp C, Riese RJ, Stern LJ, Santambrogio L: Proteomic analysis of microglia-derived exosomes: metabolic role of the aminopeptidase CD13 in neuropeptide catabolism. J Immunol 2005;175:2237-2243.
PMID: 16081791


29 Lachenal G, Pernet-Gallay K, Chivet M, Hemming FJ, Belly A, Bodon G, Blot B, Haase G, Goldberg Y, Sadoul R: Release of exosomes from differentiated neurons and its regulation by synaptic glutamatergic activity. Mol Cell Neurosci 2011;46:409-418.
PMID: 21111824


30 Gosselin RD, Meylan P, Decosterd I: Extracellular microvesicles from astrocytes contain functional glutamate transporters: regulation by protein kinase C and cell activation. Front Cell Neurosci 2013;7:251.


31 Guescini M, Genedani S, Stocchi V, Agnati LF: Astrocytes and Glioblastoma cells release exosomes carrying mtDNA. J Neural Transm 2010;117:1-4.
PMID: 19680595


32 Krämer-Albers E-M, Bretz N, Tenzer S, Winterstein C, Möbius W, Berger H, Nave K-A, Schild H, Trotter J: Oligodendrocytes secrete exosomes containing major myelin and stress-protective proteins: Trophic support for axons? Proteomics Clin Appl 2007;1:1446-1461.
PMID: 21136642


33 Tsunemi T, Hamada K, Krainc D: ATP13A2/PARK9 regulates secretion of exosomes and α-synuclein. J Neurosci 2014;34:15281-15287.
PMID: 25392495 PMCid:PMC4228131


34 Yuyama K, Sun H, Mitsutake S, Igarashi Y: Sphingolipid-modulated exosome secretion promotes clearance of amyloid-β by microglia. J Biol Chem 2012;287:10977-10989.
PMID: 22303002 PMCid:PMC3322859


35 Goldie BJ, Dun MD, Lin M, Smith ND, Verrills NM, Dayas C V, Cairns MJ: Activity-associated miRNA are packaged in Map1b-enriched exosomes released from depolarized neurons. Nucleic Acids Res 2014;42:9195-9208.
PMID: 25053844 PMCid:PMC4132720


36 Glebov K, Löchner M, Jabs R, Lau T, Merkel O, Schloss P, Steinhäuser C, Walter J: Serotonin stimulates secretion of exosomes from microglia cells. Glia 2015;63:626-634.
PMID: 25451814


37 Hooper C, Sainz-Fuertes R, Lynham S, Hye A, Killick R, Warley A, Bolondi C, Pocock J, Lovestone S: Wnt3a induces exosome secretion from primary cultured rat microglia. BMC Neurosci 2012;13:144.
PMID: 23173708 PMCid:PMC3541220


38 Frühbeis C, Fröhlich D, Kuo WP, Amphornrat J, Thilemann S, Saab AS, Kirchhoff F, Möbius W, Goebbels S, Nave KA, Schneider A, Simons M, Klugmann M, Trotter J, Krämer-Albers EM: Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication. Barres BA, editor. PLoS Biol 2013;11:e1001604.
PMID: 23874151 PMCid:PMC3706306


39 Rajendran L, Bali J, Barr MM, Court FA, Kramer-Albers E-M, Picou F, Raposo G, van der Vos KE, van Niel G, Wang J, Breakefield XO: Emerging Roles of Extracellular Vesicles in the Nervous System. J Neurosci 2014;34:15482-15489.
PMID: 25392515 PMCid:PMC4228143


40 van Balkom BWM, de Jong OG, Smits M, Brummelman J, den Ouden K, de Bree PM, van Eijndhoven MAJ, Pegtel DM, Stoorvogel W, Würdinger T, Verhaar MC: Endothelial cells require miR-214 to secrete exosomes that suppress senescence and induce angiogenesis in human and mouse endothelial cells. Blood 2013;121:3997-4006.
PMID: 23532734


41 Gutzeit C, Nagy N, Gentile M, Lyberg K, Gumz J, Vallhov H, Puga I, Klein E, Gabrielsson S, Cerutti A, Scheynius A: Exosomes derived from Burkitt's lymphoma cell lines induce proliferation, differentiation, and class-switch recombination in B cells. J Immunol 2014;192:5852-5862.
PMID: 24829410 PMCid:PMC4174405


42 Smalheiser NR: Exosomal transfer of proteins and RNAs at synapses in the nervous system. Biol Direct 2007;2:35.
PMID: 18053135 PMCid:PMC2219957


43 Simons M, Raposo G: Exosomes - vesicular carriers for intercellular communication. Curr Opin Cell Biol 2009;21:575-581.
PMID: 19442504


44 Antonucci F, Turola E, Riganti L, Caleo M, Gabrielli M, Perrotta C, Novellino L, Clementi E, Giussani P, Viani P, Matteoli M, Verderio C: Microvesicles released from microglia stimulate synaptic activity via enhanced sphingolipid metabolism. EMBO J 2012;31:1231-1240.
PMID: 22246184 PMCid:PMC3297996


45 Wang S, Cesca F, Loers G, Schweizer M, Buck F, Benfenati F, Schachner M, Kleene R: Synapsin I is an oligomannose-carrying glycoprotein, acts as an oligomannose-binding lectin, and promotes neurite outgrowth and neuronal survival when released via glia-derived exosomes. J Neurosci 2011;31:7275-7290.
PMID: 21593312


46 Pusic AD, Pusic KM, Clayton BLL, Kraig RP: IFNγ-stimulated dendritic cell exosomes as a potential therapeutic for remyelination. J Neuroimmunol 2014;266:12-23.
PMID: 24275061 PMCid:PMC3920591


47 Williams JL, Gatson NN, Smith KM, Almad A, McTigue DM, Whitacre CC: Serum exosomes in pregnancy-associated immune modulation and neuroprotection during CNS autoimmunity. Clin Immunol 2013;149:236-243.
PMID: 23706172 PMCid:PMC3778091


48 Lopez-Verrilli MA, Picou F, Court FA: Schwann cell-derived exosomes enhance axonal regeneration in the peripheral nervous system. Glia 2013;61:1795-1806.
PMID: 24038411


49 Chivet M, Javalet C, Hemming F, Pernet-Gallay K, Laulagnier K, Fraboulet S, Sadoul R: Exosomes as a novel way of interneuronal communication. Biochem Soc Trans 2013;41:241-244.
PMID: 23356290


50 Holm MM, Kaiser J, Schwab ME: Extracellular Vesicles: Multimodal Envoys in Neural Maintenance and Repair. Trends Neurosci 2018;41:360-372.
PMID: 29605090


51 Ashley J, Cordy B, Lucia D, Fradkin LG, Budnik V, Thomson T: Retrovirus-like Gag Protein Arc1 Binds RNA and Traffics across Synaptic Boutons. Cell 2018;172:262-274.
PMID: 29328915 PMCid:PMC5793882


52 Pastuzyn ED, Day CE, Kearns RB, Kyrke-Smith M, Taibi A V, McCormick J, Yoder N, Belnap DM, Erlendsson S, Morado DR, Briggs JAG, Feschotte C, Shepherd JD: The Neuronal Gene Arc Encodes a Repurposed Retrotransposon Gag Protein that Mediates Intercellular RNA Transfer. Cell 2018;173:275.
PMID: 29570995 PMCid:PMC5923900


53 Xu B, Zhang Y, Du XF, Li J, Zi HX, Bu JW, Yan Y, Han H, Du JL: Neurons secrete miR-132-containing exosomes to regulate brain vascular integrity. Cell Res 2017;27:882-897.
PMID: 28429770 PMCid:PMC5518987


54 Bakhti M, Winter C, Simons M: Inhibition of myelin membrane sheath formation by oligodendrocyte-derived exosome-like vesicles. J Biol Chem 2011;286:787-796.
PMID: 20978131 PMCid:PMC3013037


55 Pusic AD, Kraig RP: Youth and environmental enrichment generate serum exosomes containing miR-219 that promote CNS myelination. Glia 2014;62:284-299.
PMID: 24339157 PMCid:PMC4096126


56 Ridder K, Keller S, Dams M, Rupp AK, Schlaudraff J, Del Turco D, Starmann J, Macas J, Karpova D, Devraj K, Depboylu C, Landfried B, Arnold B, Plate KH, Höglinger G, Sültmann H, Altevogt P, Momma S: Extracellular Vesicle-Mediated Transfer of Genetic Information between the Hematopoietic System and the Brain in Response to Inflammation. PLoS Biol 2014;12:e1001874.
PMID: 24893313 PMCid:PMC4043485


57 Li JJ, Wang B, Kodali MC, Chen C, Kim E, Patters BJ, Lan L, Kumar S, Wang X, Yue J, Liao FF: In vivo evidence for the contribution of peripheral circulating inflammatory exosomes to neuroinflammation. J Neuroinflammation 2018;15:8.
PMID: 29310666 PMCid:PMC5759808


58 Fitzner D, Schnaars M, van Rossum D, Krishnamoorthy G, Dibaj P, Bakhti M, Regen T, Hanisch UK, Simons M: Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis. J Cell Sci 2011;124:447-458.
PMID: 21242314


59 Fröhlich D, Kuo WP, Frühbeis C, Sun JJ, Zehendner CM, Luhmann HJ, Pinto S, Toedling J, Trotter J, Krämer-Albers EM: Multifaceted effects of oligodendroglial exosomes on neurons: impact on neuronal firing rate, signal transduction and gene regulation. Philos Trans R Soc Lond B Biol Sci 2014;369:20130510.
PMID: 25135971 PMCid:PMC4142031


60 Riganti L, Antonucci F, Gabrielli M, Prada I, Giussani P, Viani P, Valtorta F, Menna E, Matteoli M, Verderio C: Sphingosine-1-Phosphate (S1P) Impacts Presynaptic Functions by Regulating Synapsin I Localization in the Presynaptic Compartment. J Neurosci 2016;36:4624-4634.
PMID: 27098703


61 Drago F, Lombardi M, Prada I, Gabrielli M, Joshi P, Cojoc D, Franck J, Fournier I, Vizioli J, Verderio C: ATP Modifies the Proteome of Extracellular Vesicles Released by Microglia and Influences Their Action on Astrocytes. Front Pharmacol 2017;8:910.
PMID: 29321741 PMCid:PMC5733563


62 Guitart K, Loers G, Buck F, Bork U, Schachner M, Kleene R: Improvement of neuronal cell survival by astrocyte-derived exosomes under hypoxic and ischemic conditions depends on prion protein. Glia 2016;64:896-910.
PMID: 26992135


63 Ciregia F, Urbani A, Palmisano G: Extracellular Vesicles in Brain Tumors and Neurodegenerative Diseases. Front Mol Neurosci 2017;10:276.
PMID: 28912682 PMCid:PMC5583211


64 Shrivastava AN, Aperia A, Melki R, Triller A: Physico-Pathologic Mechanisms Involved in Neurodegeneration: Misfolded Protein-Plasma Membrane Interactions. Neuron 2017;95:33-50.
PMID: 28683268


65 Hwang J-Y, Aromolaran KA, Zukin RS: The emerging field of epigenetics in neurodegeneration and neuroprotection. Nat Rev Neurosci 2017;18:347-361.
PMID: 28515491 PMCid:PMC6380351


66 Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A, Petzold GC, et al.: Neuroinflammation in Alzheimer's disease. Lancet Neurol 2015;14:388-405.


67 Croese T, Furlan R: Extracellular vesicles in neurodegenerative diseases. Mol Aspects Med 2018;60:52-61.
PMID: 29137922


68 Quek C, Hill AF: The role of extracellular vesicles in neurodegenerative diseases. Biochem Biophys Res Commun 2017;483:1178-1186.
PMID: 27659705


69 Schneider A, Simons M: Exosomes: vesicular carriers for intercellular communication in neurodegenerative disorders. Cell Tissue Res 2013;352:33-47.
PMID: 22610588 PMCid:PMC3602607


70 Candelario KM, Steindler DA: The role of extracellular vesicles in the progression of neurodegenerative disease and cancer. Trends Mol Med 2014;20:368-374.
PMID: 24835084 PMCid:PMC4083510


71 Pant S, Hilton H, Burczynski ME: The multifaceted exosome: biogenesis, role in normal and aberrant cellular function, and frontiers for pharmacological and biomarker opportunities. Biochem Pharmacol 2012;83:1484-1494.
PMID: 22230477


72 Zhang L, Sheng R, Qin Z: The lysosome and neurodegenerative diseases. Acta Biochim Biophys Sin 2009;41:437-445.
PMID: 19499146


73 Alvarez-Erviti L, Seow Y, Schapira AH, Gardiner C, Sargent IL, Wood MJA, Cooper JM: Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission. Neurobiol Dis 2011;42:360-367.
PMID: 21303699 PMCid:PMC3107939


74 Danzer KM, Kranich LR, Ruf WP, Cagsal-Getkin O, Winslow AR, Zhu L, Vanderburg CR, McLean PJ: Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegener 2012;7:42.
PMID: 22920859 PMCid:PMC3483256


75 Emmanouilidou E, Melachroinou K, Roumeliotis T, Garbis SD, Ntzouni M, Margaritis LH, Stefanis L, Vekrellis K: Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J Neurosci 2010;30:6838-6851.
PMID: 20484626 PMCid:PMC3842464


76 Grey M, Dunning CJ, Gaspar R, Grey C, Brundin P, Sparr E, Linse S: Acceleration of α-synuclein aggregation by exosomes. J Biol Chem 2015;290:2969-2982.
PMID: 25425650 PMCid:PMC4317028


77 Stuendl A, Kunadt M, Kruse N, Bartels C, Moebius W, Danzer KM, Mollenhauer B, Schneider A: Induction of α-synuclein aggregate formation by CSF exosomes from patients with Parkinson's disease and dementia with Lewy bodies. Brain 2016;139:481-494.
PMID: 26647156 PMCid:PMC4805087


78 Chang C, Lang H, Geng N, Wang J, Li N, Wang X: Exosomes of BV-2 cells induced by alpha-synuclein: important mediator of neurodegeneration in PD. Neurosci Lett 2013;548:190-195.
PMID: 23792198


79 Medina M, Avila J: The role of extracellular Tau in the spreading of neurofibrillary pathology. Front Cell Neurosci 2014;8:113.


80 Guo JL, Lee VMY: Seeding of normal Tau by pathological Tau conformers drives pathogenesis of Alzheimer-like tangles. J Biol Chem 2011;286:15317-15331.
PMID: 21372138 PMCid:PMC3083182


81 Saman S, Kim W, Raya M, Visnick Y, Miro S, Saman S, Jackson B, McKee AC, Alvarez VE, Lee NCY, Hall GF: Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem 2012;287:3842-3849.
PMID: 22057275 PMCid:PMC3281682


82 Rajendran L, Honsho M, Zahn TR, Keller P, Geiger KD, Verkade P, Simons K: Alzheimer's disease beta-amyloid peptides are released in association with exosomes. Proc Natl Acad Sci USA 2006;103:11172-11177.
PMID: 16837572 PMCid:PMC1544060


83 Perez-Gonzalez R, Gauthier SA, Kumar A, Levy E: The exosome secretory pathway transports amyloid precursor protein carboxyl-terminal fragments from the cell into the brain extracellular space. J Biol Chem 2012;287:43108-43115.
PMID: 23129776 PMCid:PMC3522305


84 Sharples RA, Vella LJ, Nisbet RM, Naylor R, Perez K, Barnham KJ, Masters CL, Hill AF: Inhibition of gamma-secretase causes increased secretion of amyloid precursor protein C-terminal fragments in association with exosomes. FASEB J 2008;22:1469-1478.
PMID: 18171695


85 Falker C, Hartmann A, Guett I, Dohler F, Altmeppen H, Betzel C, Schubert R, Thurm D, Wegwitz F, Joshi P, Verderio C, Krasemann S, Glatzel M: Exosomal cellular prion protein drives fibrillization of amyloid beta and counteracts amyloid beta-mediated neurotoxicity. J Neurochem 2016;137:88-100.
PMID: 26710111


86 Yuyama K, Sun H, Sakai S, Mitsutake S, Okada M, Tahara H, Furukawa J-I, Fujitani N, Shinohara Y, Igarashi Y: Decreased amyloid-β pathologies by intracerebral loading of glycosphingolipid-enriched exosomes in Alzheimer model mice. J Biol Chem 2014;289:24488-24498.
PMID: 25037226 PMCid:PMC4148874


87 Eitan E, Hutchison ER, Marosi K, Comotto J, Mustapic M, Nigam SM, Suire C, Maharana C, Jicha GA, Liu D, Machairaki V, Witwer KW, Kapogiannis D, Mattson MP: Extracellular vesicle-associated Aβ mediates trans-neuronal bioenergetic and Ca2+-handling deficits in Alzheimer's disease models. npj Aging Mech Dis 2016;2:16019.
PMID: 27928512 PMCid:PMC5137253


88 Gomes C, Keller S, Altevogt P, Costa J: Evidence for secretion of Cu,Zn superoxide dismutase via exosomes from a cell model of amyotrophic lateral sclerosis. Neurosci Lett 2007;428:43-46.
PMID: 17942226


89 Münch C, O'Brien J, Bertolotti A: Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells. Proc Natl Acad Sci 2011;108:3548-3553.
PMID: 21321227 PMCid:PMC3048161


90 Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VMY: Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis. Science 2006;314:130-133.
PMID: 17023659


91 Nonaka T, Masuda-Suzukake M, Arai T, Hasegawa Y, Akatsu H, Obi T, Yoshida M, Murayama S, Mann DMA, Akiyama H, Hasegawa M: Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell Rep 2013;4:124-134.
PMID: 23831027


92 Bellingham SA, Coleman BM, Hill AF: Small RNA deep sequencing reveals a distinct miRNA signature released in exosomes from prion-infected neuronal cells. Nucleic Acids Res 2012;40:10937-10949.
PMID: 22965126 PMCid:PMC3505968


93 Cheng L, Sharples RA, Scicluna BJ, Hill AF: Exosomes provide a protective and enriched source of miRNA for biomarker profiling compared to intracellular and cell-free blood. J Extracell Vesicles 2014;3:23743.
PMID: 24683445 PMCid:PMC3968297


94 Montecalvo A, Larregina AT, Shufesky WJ, Stolz DB, Sullivan MLG, Karlsson JM, Baty CJ, Gibson GA, Erdos G, Wang Z, Milosevic J, Tkacheva OA, Divito SJ, Jordan R, Lyons-Weiler J, Watkins SC, Morelli AE: Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood 2012;119:756-766.
PMID: 22031862 PMCid:PMC3265200


95 Koga Y, Yasunaga M, Moriya Y, Akasu T, Fujita S, Yamamoto S, Matsumura Y: Exosome can prevent RNase from degrading microRNA in feces. J Gastrointest Oncol 2011;2:215-222.


96 Bellingham SA, Guo BB, Coleman BM, Hill AF: Exosomes: vehicles for the transfer of toxic proteins associated with neurodegenerative diseases? Front Physiol 2012;3:124.
PMID: 22563321 PMCid:PMC3342525


97 Vella LJ, Sharples RA, Nisbet RM, Cappai R, Hill AF: The role of exosomes in the processing of proteins associated with neurodegenerative diseases. Eur Biophys J 2008;37:323-332.
PMID: 18064447


98 Bagga S, Bracht J, Hunter S, Massirer K, Holtz J, Eachus R, Pasquinelli AE: Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell 2005;122:553-563.
PMID: 16122423


99 Lai EC: Micro RNAs are complementary to 3' UTR sequence motifs that mediate negative post-transcriptional regulation. Nat Genet 2002;30:363-364.
PMID: 11896390


100 Cogswell JP, Ward J, Taylor IA, Waters M, Shi Y, Cannon B, Kelnar K, Kemppainen J, Brown D, Chen C, Prinjha RK, Richardson JC, Saunders AM, Roses AD, Richards CA: Identification of miRNA changes in Alzheimer's disease brain and CSF yields putative biomarkers and insights into disease pathways. J Alzheimers Dis 2008;14:27-41.


101 Hébert SS, Wang WX, Zhu Q, Nelson PT: A study of small RNAs from cerebral neocortex of pathology-verified Alzheimer's disease, dementia with lewy bodies, hippocampal sclerosis, frontotemporal lobar dementia, and non-demented human controls. J Alzheimers Dis 2013;35:335-348.
PMID: 23403535 PMCid:PMC3753694


102 Lau P, Frigerio CS, De Strooper B: Variance in the identification of microRNAs deregulated in Alzheimer's disease and possible role of lincRNAs in the pathology: the need of larger datasets. Ageing Res Rev 2014;17:43-53.
PMID: 24607832


103 Wong HKA, Veremeyko T, Patel N, Lemere CA, Walsh DM, Esau C, Vanderburg C, Krichevsky AM: De-repression of FOXO3a death axis by microRNA-132 and -212 causes neuronal apoptosis in Alzheimer's disease. Hum Mol Genet 2013;22:3077-3092.
PMID: 23585551


104 Chen-Plotkin AS, Unger TL, Gallagher MD, Bill E, Kwong LK, Volpicelli-Daley L, Busch JI, Akle S, Grossman M, Van Deerlin V, Trojanowski JQ, Lee VM-Y: TMEM106B, the risk gene for frontotemporal dementia, is regulated by the microRNA-132/212 cluster and affects progranulin pathways. J Neurosci 2012;32:11213-11227.
PMID: 22895706 PMCid:PMC3446826


105 Shah R, Patel T, Freedman JE: Circulating Extracellular Vesicles in Human Disease. N Engl J Med 2018;379:958-966.
PMID: 30184457


106 Gui Y, Liu H, Zhang L, Lv W, Hu X: Altered microRNA profiles in cerebrospinal fluid exosome in Parkinson disease and Alzheimer disease. Oncotarget 2015;6:37043-37053.


107 Compston A, Coles A: Multiple sclerosis. Lancet 2008;372:1502-1517.


108 Dendrou CA, Fugger L, Friese MA: Immunopathology of multiple sclerosis. Nat Rev Immunol 2015;15:545-558.
PMID: 26250739


109 Scolding NJ, Morgan BP, Houston WA, Linington C, Campbell AK, Compston DA: Vesicular removal by oligodendrocytes of membrane attack complexes formed by activated complement. Nature 1989;339:620-622.
PMID: 2733792


110 Wheway J, Latham SL, Combes V, Grau GER: Endothelial microparticles interact with and support the proliferation of T cells. J Immunol 2014;193:3378-3387.
PMID: 25187656 PMCid:PMC4170003


111 Verderio C, Muzio L, Turola E, Bergami A, Novellino L, Ruffini F, Riganti L, Corradini I, Francolini M, Garzetti L, Maiorino C, Servida F, Vercelli A, Rocca M, Dalla Libera D, Martinelli V, Comi G, Martino G, Matteoli M, Furlan R: Myeloid microvesicles are a marker and therapeutic target for neuroinflammation. Ann Neurol 2012;72:610-624.
PMID: 23109155


112 Minagar A, Jy W, Jimenez JJ, Sheremata WA, Mauro LM, Mao WW, Horstman LL, Ahn YS: Elevated plasma endothelial microparticles in multiple sclerosis. Neurology 2001;56:1319-1324.
PMID: 11376181


113 Alexander JS, Chervenak R, Weinstock-Guttman B, Tsunoda I, Ramanathan M, Martinez N, Omura S, Sato F, Chaitanya GV, Minagar A, McGee J, Jennings MH, Monceaux C, Becker F, Cvek U, Trutschl M, Zivadinov R: Blood circulating microparticle species in relapsing-remitting and secondary progressive multiple sclerosis. A case-control, cross sectional study with conventional MRI and advanced iron content imaging outcomes. J Neurol Sci 2015;355:84-89.
PMID: 26073484 PMCid:PMC4550483


114 Marcos-Ramiro B, Oliva Nacarino P, Serrano-Pertierra E, Blanco-Gelaz MA, Weksler BB, Romero IA, Couraud PO, Tuńón A, López-Larrea C, Millán J, Cernuda-Morollón E: Microparticles in multiple sclerosis and clinically isolated syndrome: effect on endothelial barrier function. BMC Neurosci 2014;15:110.
PMID: 25242463 PMCid:PMC4261570


115 Sheremata WA, Jy W, Horstman LL, Ahn YS, Alexander JS, Minagar A: Evidence of platelet activation in multiple sclerosis. J Neuroinflammation 2008;5:27.
PMID: 18588683 PMCid:PMC2474601


116 Jy W, Minagar A, Jimenez JJ, Sheremata WA, Mauro LM, Horstman LL, Bidot C, Ahn YS: Endothelial microparticles (EMP) bind and activate monocytes: elevated EMP-monocyte conjugates in multiple sclerosis. Front Biosci 2004;9:3137-3144.
PMID: 15353343


117 Sáenz-Cuesta M, Irizar H, Castillo-Trivińo T, Muńoz-Culla M, Osorio-Querejeta I, Prada A, Sepúlveda L, López-Mato MP, López de Munain A, Comabella M, Villar LM, Olascoaga J, Otaegui D: Circulating microparticles reflect treatment effects and clinical status in multiple sclerosis. Biomark Med 2014;8:653-661.
PMID: 25123034


118 Selmaj I, Cichalewska M, Namiecinska M, Galazka G, Horzelski W, Selmaj KW, Mycko MP: Global exosome transcriptome profiling reveals biomarkers for multiple sclerosis. Ann Neurol 2017;81:703-717.
PMID: 28411393


119 Gatson NN, Williams JL, Powell ND, McClain MA, Hennon TR, Robbins PD, Whitacre CC: Induction of pregnancy during established EAE halts progression of CNS autoimmune injury via pregnancy-specific serum factors. J Neuroimmunol 2011;230:105-113.
PMID: 20950868 PMCid:PMC3021646


120 Langer-Gould A, Garren H, Slansky A, Ruiz PJ, Steinman L: Late pregnancy suppresses relapses in experimental autoimmune encephalomyelitis: evidence for a suppressive pregnancy-related serum factor. J Immunol 2002;169:1084-1091.
PMID: 12097417


121 McClain MA, Gatson NN, Powell ND, Papenfuss TL, Gienapp IE, Song F, Shawler TM, Kithcart A, Whitacre CC: Pregnancy suppresses experimental autoimmune encephalomyelitis through immunoregulatory cytokine production. J Immunol 2007;179:8146-8152.
PMID: 18056357


122 Xin H, Li Y, Cui Y, Yang JJ, Zhang ZG, Chopp M: Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab 2013;33:1711-1715.
PMID: 23963371 PMCid:PMC3824189


123 Levine DA, Galecki AT, Langa KM, Unverzagt FW, Kabeto MU, Giordani B, Wadley VG: Trajectory of Cognitive Decline After Incident Stroke. JAMA 2015;314:41-51.
PMID: 26151265 PMCid:PMC4655087


124 Liu Y, Zhang J, Han R, Liu H, Sun D, Liu X: Downregulation of serum brain specific microRNA is associated with inflammation and infarct volume in acute ischemic stroke. J Clin Neurosci 2015;22:291-295.
PMID: 25257664


125 Xin H, Li Y, Buller B, Katakowski M, Zhang Y, Wang X, Shang X, Zhang ZG, Chopp M: Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells 2012;30:1556-1564.
PMID: 22605481 PMCid:PMC3495063


126 Laskowitz DT, Kasner SE, Saver J, Remmel KS, Jauch EC, BRAIN Study Group: Clinical usefulness of a biomarker-based diagnostic test for acute stroke: the Biomarker Rapid Assessment in Ischemic Injury (BRAIN) study. Stroke 2009;40:77-85.
PMID: 18948614


127 Kucharzewska P, Christianson HC, Welch JE, Svensson KJ, Fredlund E, Ringnér M, Mörgelin M, Bourseau-Guilmain E, Bengzon J, Belting M: Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development. Proc Natl Acad Sci U S A 2013;110:7312-7317.
PMID: 23589885 PMCid:PMC3645587


128 Manterola L, Guruceaga E, Gállego Pérez-Larraya J, González-Huarriz M, Jauregui P, Tejada S, Diez-Valle R, Segura V, Samprón N, Barrena C, Ruiz I, Agirre A, Ayuso A, Rodríguez J, González A, Xipell E, Matheu A, López de Munain A, Tuńón T, Zazpe I, García-Foncillas J, Paris S, et al.: A small noncoding RNA signature found in exosomes of GBM patient serum as a diagnostic tool. Neuro Oncol 2014;16:520-527.
PMID: 24435880 PMCid:PMC3956347


129 Li CCY, Eaton SA, Young PE, Lee M, Shuttleworth R, Humphreys DT, Grau GE, Combes V, Bebawy M, Gong J, Brammah S, Buckland ME, Suter CM: Glioma microvesicles carry selectively packaged coding and non-coding RNAs which alter gene expression in recipient cells. RNA Biol 2013;10:1333-1344.
PMID: 23807490 PMCid:PMC3817155


130 Skog J, Würdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, Curry WT, Carter BS, Krichevsky AM, Breakefield XO: Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 2008;10:1470-1476.
PMID: 19011622 PMCid:PMC3423894


131 Peinado H, Alečković M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, García-Santos G, Ghajar CM, Nitadori-Hoshino A, Hoffman C, Badal K, Garcia BA, Callahan MK, Yuan J, Martins VR, Skog J, Kaplan RN, Brady MS, et al.: Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 2012;18:883-891.
PMID: 22635005 PMCid:PMC3645291


132 Breakefield XO, Frederickson RM, Simpson RJ: Gesicles: Microvesicle "cookies" for transient information transfer between cells. Mol Ther 2011;19:1574-1576.
PMID: 21886114 PMCid:PMC3182359


133 Taylor DD, Gerçel-Taylor C: Tumour-derived exosomes and their role in cancer-associated T-cell signalling defects. Br J Cancer 2005;92:305-311.
PMID: 15655551 PMCid:PMC2361848


134 De Flora S, Bonanni P: The prevention of infection-associated cancers. Carcinogenesis 2011;32:787-795.
PMID: 21436188 PMCid:PMC3314281


135 Roccaro AM, Sacco A, Maiso P, Azab AK, Tai YT, Reagan M, Azab F, Flores LM, Campigotto F, Weller E, Anderson KC, Scadden DT, Ghobrial IM: BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression. J Clin Invest 2013;123:1542-1555.
PMID: 23454749 PMCid:PMC3613927


136 Sheldon H, Heikamp E, Turley H, Dragovic R, Thomas P, Oon CE, Leek R, Edelmann M, Kessler B, Sainson RCA, Sargent I, Li JL, Harris AL: New mechanism for Notch signaling to endothelium at a distance by Delta-like 4 incorporation into exosomes. Blood 2010;116:2385-2394.
PMID: 20558614


137 Gould SJ, Raposo G: As we wait: coping with an imperfect nomenclature for extracellular vesicles. J Extracell Vesicles 2013;2:20389.
PMID: 24009890 PMCid:PMC3760635