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      Ectosomes: A New Mechanism for Non-Exosomal Secretion of Tau Protein

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          Abstract

          Tau is a microtubule-associated protein that aggregates in neurodegenerative disorders known as tauopathies. Recently, studies have suggested that Tau may be secreted and play a role in neural network signalling. However, once deregulated, secreted Tau may also participate in the spreading of Tau pathology in hierarchical pathways of neurodegeneration. The mechanisms underlying neuron-to-neuron Tau transfer are still unknown; given the known role of extra-cellular vesicles in cell-to-cell communication, we wondered whether these vesicles could carry secreted Tau. We found, among vesicles, that Tau is predominately secreted in ectosomes, which are plasma membrane-originating vesicles, and when it accumulates, the exosomal pathway is activated.

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          Tau protein isoforms, phosphorylation and role in neurodegenerative disorders.

          L Buée, T Bussière, V Buée-Scherrer … (2000)
          Tau proteins belong to the family of microtubule-associated proteins. They are mainly expressed in neurons where they play an important role in the assembly of tubulin monomers into microtubules to constitute the neuronal microtubules network. Microtubules are involved in maintaining the cell shape and serve as tracks for axonal transport. Tau proteins also establish some links between microtubules and other cytoskeletal elements or proteins. Tau proteins are translated from a single gene located on chromosome 17. Their expression is developmentally regulated by an alternative splicing mechanism and six different isoforms exist in the human adult brain. Tau proteins are the major constituents of intraneuronal and glial fibrillar lesions described in Alzheimer's disease and numerous neurodegenerative disorders referred to as 'tauopathies'. Molecular analysis has revealed that an abnormal phosphorylation might be one of the important events in the process leading to their aggregation. Moreover, a specific set of pathological tau proteins exhibiting a typical biochemical pattern, and a different regional and laminar distribution could characterize each of these disorders. Finally, a direct correlation has been established between the progressive involvement of the neocortical areas and the increasing severity of dementia, suggesting that pathological tau proteins are reliable marker of the neurodegenerative process. The recent discovery of tau gene mutations in frontotemporal dementia with parkinsonism linked to chromosome 17 has reinforced the predominant role attributed to tau proteins in the pathogenesis of neurodegenerative disorders, and underlined the fact that distinct sets of tau isoforms expressed in different neuronal populations could lead to different pathologies.
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            Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles.

            S Amigorena, P Véron, Y Garin … (2001)
            Dendritic cells constitutively secrete a population of small (50-90 nm diameter) Ag-presenting vesicles called exosomes. When sensitized with tumor antigenic peptides, dendritic cells produce exosomes, which stimulate anti-tumor immune responses and the rejection of established tumors in mice. Using a systematic proteomic approach, we establish the first extensive protein map of a particular exosome population; 21 new exosomal proteins were thus identified. Most proteins present in exosomes are related to endocytic compartments. New exosomal residents include cytosolic proteins most likely involved in exosome biogenesis and function, mainly cytoskeleton-related (cofilin, profilin I, and elongation factor 1alpha) and intracellular membrane transport and signaling factors (such as several annexins, rab 7 and 11, rap1B, and syntenin). Importantly, we also identified a novel category of exosomal proteins related to apoptosis: thioredoxin peroxidase II, Alix, 14-3-3, and galectin-3. These findings led us to analyze possible structural relationships between exosomes and microvesicles released by apoptotic cells. We show that although they both represent secreted populations of membrane vesicles relevant to immune responses, exosomes and apoptotic vesicles are biochemically and morphologically distinct. Therefore, in addition to cytokines, dendritic cells produce a specific population of membrane vesicles, exosomes, with unique molecular composition and strong immunostimulating properties.
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              Trans-cellular propagation of Tau aggregation by fibrillar species.

              Najla Kfoury, Brandon Holmes, Hong Jiang … (2012)
              Aggregation of the microtubule associated protein Tau is associated with several neurodegenerative disorders, including Alzheimer disease and frontotemporal dementia. In Alzheimer disease, Tau pathology spreads progressively throughout the brain, possibly along existing neural networks. However, it is still unclear how the propagation of Tau misfolding occurs. Intriguingly, in animal models, vaccine-based therapies have reduced Tau and synuclein pathology by uncertain mechanisms, given that these proteins are intracellular. We have previously speculated that trans-cellular propagation of misfolding could be mediated by a process similar to prion pathogenesis, in which fibrillar Tau aggregates spread pathology from cell to cell. However, there has been little evidence to demonstrate true trans-cellular propagation of Tau misfolding, in which Tau aggregates from one cell directly contact Tau protein in the recipient cell to trigger further aggregation. Here we have observed that intracellular Tau fibrils are directly released into the medium and then taken up by co-cultured cells. Internalized Tau aggregates induce fibrillization of intracellular Tau in these naive recipient cells via direct protein-protein contact that we demonstrate using FRET. Tau aggregation can be amplified across several generations of cells. An anti-Tau monoclonal antibody blocks Tau aggregate propagation by trapping fibrils in the extracellular space and preventing their uptake. Thus, propagation of Tau protein misfolding among cells can be mediated by release and subsequent uptake of fibrils that directly contact native protein in recipient cells. These results support the model of aggregate propagation by templated conformational change and suggest a mechanism for vaccine-based therapies in neurodegenerative diseases.
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                Author and article information

                Contributors
                Jesus Avila: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2014
                Publication date (Electronic): 27 June 2014
                Volume: 9
                Issue: 6
                Electronic Location Identifier: e100760
                Affiliations
                [1 ]Inserm, UMR837, Lille, France
                [2 ]Université de Lille, Faculté de Médecine, IMPRT, JPARC, Lille, France
                [3 ]CMRR, CHR, Lille, France
                [4 ]Laboratoire d′Enzymologie et Biochimie Structurales, UPR 3082 CNRS, Gif-sur-Yvette, France
                [5 ]Atomic Energy Commission (CEA), Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), Fontenay-aux-Roses, France
                [6 ]CNRS, URA2210, Molecular Imaging Research Center (MIRCen), Fontenay-aux-Roses, France
                CSIC/Universidad Autonoma Madrid, Spain
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MC SD L. Buée. Performed the experiments: GA SB L. Bousset EB RC SC LD SD MCG CL AL MC. Analyzed the data: EB PH MC SD L. Buée. Contributed reagents/materials/analysis tools: L. Bousset EB RM. Wrote the paper: MC L. Buée.

                Article
                Publisher ID: PONE-D-14-05491
                DOI: 10.1371/journal.pone.0100760
                PMC ID: 4074092
                PubMed ID: 24971751
                SO-VID: 3e47d3ea-e4e6-4c91-a4ac-a3dea1677571
                Copyright statement: Copyright @ 2014
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 5 February 2014
                Date accepted : 28 May 2014
                Page count
                Pages: 10
                Funding
                This work was supported through the LabEx DISTALZ (an excellent laboratory- Development of Innovative Strategies for a Transdisciplinary Approach to Alzheimer's disease), the FUI MEDIALZ and CPER DN2M (VICTAUR), Inserm, CNRS, University of Lille 2, Lille Métropole Communauté Urbaine (LMCU), Région Nord/Pas-de-Calais, FEDER and the ‘Fondation Plan Alzheimer’ (PRIMATAU). We thank the IMPRT (Lille) for access to core facilities (animal housing, D. Taillieu; EM, C. Allet). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Body Fluids
                Subject: Fluid Physiology
                Subject: Nervous System
                Subject: Cell Biology
                Subject: Cell Physiology
                Subject: Neuroscience
                Subject: Cellular Neuroscience
                Subject: Neural Networks
                Subject: Systems Biology

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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