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Extracellular Vesicles as a Source of Biomarkers for Neurodegenerative Disorders...
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Extracellular Vesicles as a Source of Biomarkers for Neurodegenerative Disorders Propagation

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (15 January 2023) | Viewed by 23476

Special Issue Editors

Dr. Carla Lopes

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Guest Editor
Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
Interests: neurodegenerative diseases; extracellular vesicles; Mitochondrial dysfunction; neurodegeneration; oxidative stress; neuroprotection
Dr. Sandra Mota

E-Mail Website
Guest Editor
Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
Interests: neurodegenerative disorders; synaptic dysfunction; neurodegeneration; oxidative stress; neuroprotection; mitochondrial dysfunction
Dr. Elisabete Ferreiro

E-Mail Website
Guest Editor
Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
Interests: neurodegenerative disorders; amyotrophic lateral sclerosis; neurogenesis; mitochondrial dysfunction

Special Issue Information

Dear Colleagues,

Extracellular vesicles (EVs) are membrane-enclosed nanosized particles released by cells that participate in intercellular communication through the transfer of biological material. EVs include exosomes that are small vesicles, ranging in size from 50 to 100 nm; they function as natural carriers of a wide variety of genetic material and proteins. Indeed, exosomes appear to be involved in intercellular communication and the maintenance of intracellular homeostasis. Their involvement in health and age-associated processes is critical for several neurological diseases. Exosomes of specific cell origins can provide important information about promising biomarkers for a myriad of diseases. The accumulation of protein aggregates is a common pathological hallmark in many neurodegenerative diseases, including Alzheimer Disease, Parkinson Disease, Huntington Disease, Amyotrophic Lateral Sclerosis and prion diseases. Because exosomes transport damaged cellular material, they eventually contribute to the spreading mechanism of pathological misfolded proteins within the brain, thus promoting the neurodegeneration process.

The aim of this Special Issue is to provide an overview of novel discoveries in the emerging field of EVs, the role of exosomes in CNS homeostasis, their possible contributions in the development of neurodegenerative diseases, and the effectiveness of exosome cargo as biomarkers of disease.

Dr. Carla Lopes
Dr. Sandra Mota
Dr. Elisabete Ferreiro
Guest Editors

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Keywords

  • extracellular vesicles
  • biomarkers
  • neurodegenerative disorders
  • neuronally derived exosomes
  • signaling
  • propagation

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Published Papers (5 papers)

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Research

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36 pages, 7159 KiB  
Article
Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease
by Gonçalo Garcia, Sara Pinto, Sofia Ferreira, Daniela Lopes, Maria João Serrador, Adelaide Fernandes, Ana Rita Vaz, Alexandre de Mendonça, Frank Edenhofer, Tarja Malm, Jari Koistinaho and Dora Brites
Cells 2022, 11(21), 3377; https://doi.org/10.3390/cells11213377 - 26 Oct 2022
Cited by 17 | Viewed by 5423
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder associated with neuron–glia dysfunction and dysregulated miRNAs. We previously reported upregulated miR-124/miR-21 in AD neurons and their exosomes. However, their glial distribution, phenotypic alterations and exosomal spread are scarcely documented. Here, we show glial cell activation [...] Read more.
Alzheimer’s disease (AD) is a neurodegenerative disorder associated with neuron–glia dysfunction and dysregulated miRNAs. We previously reported upregulated miR-124/miR-21 in AD neurons and their exosomes. However, their glial distribution, phenotypic alterations and exosomal spread are scarcely documented. Here, we show glial cell activation and miR-21 overexpression in mouse organotypic hippocampal slices transplanted with SH-SY5Y cells expressing the human APP695 Swedish mutation. The upregulation of miR-21 only in the CSF from a small series of mild cognitive impairment (MCI) AD patients, but not in non-AD MCI individuals, supports its discriminatory potential. Microglia, neurons, and astrocytes differentiated from the same induced pluripotent stem cells from PSEN1ΔE9 AD patients all showed miR-21 elevation. In AD neurons, miR-124/miR-21 overexpression was recapitulated in their exosomes. In AD microglia, the upregulation of iNOS and miR-21/miR-146a supports their activation. AD astrocytes manifested a restrained inflammatory profile, with high miR-21 but low miR-155 and depleted exosomal miRNAs. Their immunostimulation with C1q + IL-1α + TNF-α induced morphological alterations and increased S100B, inflammatory transcripts, sAPPβ, cytokine release and exosomal miR-21. PPARα, a target of miR-21, was found to be repressed in all models, except in neurons, likely due to concomitant miR-125b elevation. The data from these AD models highlight miR-21 as a promising biomarker and a disease-modifying target to be further explored. Full article
(This article belongs to the Special Issue Extracellular Vesicles as a Source of Biomarkers for Neurodegenerative Disorders Propagation)
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15 pages, 2254 KiB  
Article
The Neurotoxicity of Vesicles Secreted by ALS Patient Myotubes Is Specific to Exosome-Like and Not Larger Subtypes
by Ekene Anakor, Vanessa Milla, Owen Connolly, Cecile Martinat, Pierre Francois Pradat, Julie Dumonceaux, William Duddy and Stephanie Duguez
Cells 2022, 11(5), 845; https://doi.org/10.3390/cells11050845 - 1 Mar 2022
Cited by 9 | Viewed by 4273
Abstract
Extracellular vesicles can mediate communication between tissues, affecting the physiological conditions of recipient cells. They are increasingly investigated in Amyotrophic Lateral Sclerosis, the most common form of Motor Neurone Disease, as transporters of misfolded proteins including SOD1, FUS, TDP43, or other neurotoxic elements, [...] Read more.
Extracellular vesicles can mediate communication between tissues, affecting the physiological conditions of recipient cells. They are increasingly investigated in Amyotrophic Lateral Sclerosis, the most common form of Motor Neurone Disease, as transporters of misfolded proteins including SOD1, FUS, TDP43, or other neurotoxic elements, such as the dipeptide repeats resulting from C9orf72 expansions. EVs are classified based on their biogenesis and size and can be separated by differential centrifugation. They include exosomes, released by the fusion of multivesicular bodies with the plasma membrane, and ectosomes, also known as microvesicles or microparticles, resulting from budding or pinching of the plasma membrane. In the current study, EVs were obtained from the myotube cell culture medium of ALS patients or healthy controls. EVs of two different sizes, separating at 20,000 or 100,000 g, were then compared in terms of their effects on recipient motor neurons, astrocytes, and myotubes. Compared to untreated cells, the smaller, exosome-like vesicles of ALS patients reduced the survival of motor neurons by 31% and of myotubes by 18%, decreased neurite length and branching, and increased the proportion of stellate astrocytes, whereas neither those of healthy subjects, nor larger EVs of ALS or healthy subjects, had such effects. Full article
(This article belongs to the Special Issue Extracellular Vesicles as a Source of Biomarkers for Neurodegenerative Disorders Propagation)
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19 pages, 3160 KiB  
Article
Neurodegenerative Disease-Associated TDP-43 Fragments Are Extracellularly Secreted with CASA Complex Proteins
by Elena Casarotto, Daisy Sproviero, Eleonora Corridori, Maria Cristina Gagliani, Marta Cozzi, Marta Chierichetti, Riccardo Cristofani, Veronica Ferrari, Mariarita Galbiati, Francesco Mina, Margherita Piccolella, Paola Rusmini, Barbara Tedesco, Stella Gagliardi, Katia Cortese, Cristina Cereda, Angelo Poletti and Valeria Crippa
Cells 2022, 11(3), 516; https://doi.org/10.3390/cells11030516 - 2 Feb 2022
Cited by 14 | Viewed by 3751
Abstract
Extracellular vesicles (EVs) play a central role in neurodegenerative diseases (NDs) since they may either spread the pathology or contribute to the intracellular protein quality control (PQC) system for the cellular clearance of NDs-associated proteins. Here, we investigated the crosstalk between large (LVs) [...] Read more.
Extracellular vesicles (EVs) play a central role in neurodegenerative diseases (NDs) since they may either spread the pathology or contribute to the intracellular protein quality control (PQC) system for the cellular clearance of NDs-associated proteins. Here, we investigated the crosstalk between large (LVs) and small (SVs) EVs and PQC in the disposal of TDP-43 and its FTLD and ALS-associated C-terminal fragments (TDP-35 and TDP-25). By taking advantage of neuronal cells (NSC-34 cells), we demonstrated that both EVs types, but particularly LVs, contained TDP-43, TDP-35 and TDP-25. When the PQC system was inhibited, as it occurs in NDs, we found that TDP-35 and TDP-25 secretion via EVs increased. In line with this observation, we specifically detected TDP-35 in EVs derived from plasma of FTLD patients. Moreover, we demonstrated that both neuronal and plasma-derived EVs transported components of the chaperone-assisted selective autophagy (CASA) complex (HSP70, BAG3 and HSPB8). Neuronal EVs also contained the autophagy-related MAP1LC3B-II protein. Notably, we found that, under PQC inhibition, HSPB8, BAG3 and MAP1LC3B-II secretion paralleled that of TDP-43 species. Taken together, our data highlight the role of EVs, particularly of LVs, in the disposal of disease-associated TDP-43 species, and suggest a possible new role for the CASA complex in NDs. Full article
(This article belongs to the Special Issue Extracellular Vesicles as a Source of Biomarkers for Neurodegenerative Disorders Propagation)
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Review

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35 pages, 1006 KiB  
Review
Recent Advances in Extracellular Vesicles in Amyotrophic Lateral Sclerosis and Emergent Perspectives
by Gonçalo J. M. Afonso, Carla Cavaleiro, Jorge Valero, Sandra I. Mota and Elisabete Ferreiro
Cells 2023, 12(13), 1763; https://doi.org/10.3390/cells12131763 - 1 Jul 2023
Cited by 8 | Viewed by 3703
Abstract
Amyotrophic lateral sclerosis (ALS) is a severe and incurable neurodegenerative disease characterized by the progressive death of motor neurons, leading to paralysis and death. It is a rare disease characterized by high patient-to-patient heterogeneity, which makes its study arduous and complex. Extracellular vesicles [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a severe and incurable neurodegenerative disease characterized by the progressive death of motor neurons, leading to paralysis and death. It is a rare disease characterized by high patient-to-patient heterogeneity, which makes its study arduous and complex. Extracellular vesicles (EVs) have emerged as important players in the development of ALS. Thus, ALS phenotype-expressing cells can spread their abnormal bioactive cargo through the secretion of EVs, even in distant tissues. Importantly, owing to their nature and composition, EVs’ formation and cargo can be exploited for better comprehension of this elusive disease and identification of novel biomarkers, as well as for potential therapeutic applications, such as those based on stem cell-derived exosomes. This review highlights recent advances in the identification of the role of EVs in ALS etiopathology and how EVs can be promising new therapeutic strategies. Full article
(This article belongs to the Special Issue Extracellular Vesicles as a Source of Biomarkers for Neurodegenerative Disorders Propagation)
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22 pages, 1393 KiB  
Review
Mitochondrial Damage-Associated Molecular Patterns Content in Extracellular Vesicles Promotes Early Inflammation in Neurodegenerative Disorders
by Cláudia M. Deus, Henrique Tavares, Margarida Beatriz, Sandra Mota and Carla Lopes
Cells 2022, 11(15), 2364; https://doi.org/10.3390/cells11152364 - 1 Aug 2022
Cited by 30 | Viewed by 5193
Abstract
Neuroinflammation is a common hallmark in different neurodegenerative conditions that share neuronal dysfunction and a progressive loss of a selectively vulnerable brain cell population. Alongside ageing and genetics, inflammation, oxidative stress and mitochondrial dysfunction are considered key risk factors. Microglia are considered immune [...] Read more.
Neuroinflammation is a common hallmark in different neurodegenerative conditions that share neuronal dysfunction and a progressive loss of a selectively vulnerable brain cell population. Alongside ageing and genetics, inflammation, oxidative stress and mitochondrial dysfunction are considered key risk factors. Microglia are considered immune sentinels of the central nervous system capable of initiating an innate and adaptive immune response. Nevertheless, the pathological mechanisms underlying the initiation and spread of inflammation in the brain are still poorly described. Recently, a new mechanism of intercellular signalling mediated by small extracellular vesicles (EVs) has been identified. EVs are nanosized particles (30–150 nm) with a bilipid membrane that carries cell-specific bioactive cargos that participate in physiological or pathological processes. Damage-associated molecular patterns (DAMPs) are cellular components recognised by the immune receptors of microglia, inducing or aggravating neuroinflammation in neurodegenerative disorders. Diverse evidence links mitochondrial dysfunction and inflammation mediated by mitochondrial-DAMPs (mtDAMPs) such as mitochondrial DNA, mitochondrial transcription factor A (TFAM) and cardiolipin, among others. Mitochondrial-derived vesicles (MDVs) are a subtype of EVs produced after mild damage to mitochondria and, upon fusion with multivesicular bodies are released as EVs to the extracellular space. MDVs are particularly enriched in mtDAMPs which can induce an immune response and the release of pro-inflammatory cytokines. Importantly, growing evidence supports the association between mitochondrial dysfunction, EV release and inflammation. Here, we describe the role of extracellular vesicles-associated mtDAMPS in physiological conditions and as neuroinflammation activators contributing to neurodegenerative disorders. Full article
(This article belongs to the Special Issue Extracellular Vesicles as a Source of Biomarkers for Neurodegenerative Disorders Propagation)
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